David A. Solomon

All Publications

• Longitudinal multimodal profiling of IDH-wildtype glioblastoma reveals the molecular evolution and cellular phenotypes underlying prognostically different treatment responses. Neuro-oncology Lucas, C. G., Al-Adli, N. N., Young, J. S., Gupta, R., Morshed, R. A., Wu, J., Ravindranathan, A., Shai, A., Oberheim Bush, N. A., Taylor, J. W., de Groot, J., Villanueva-Meyer, J. E., Pekmezci, M., Perry, A., Bollen, A. W., Theodosopoulos, P. V., Aghi, M. K., Chang, E. F., Hervey-Jumper, S. L., Raleigh, D. R., Molinaro, A. M., Costello, J. F., Diaz, A. A., Clarke, J. L., Butowski, N. A., Phillips, J. J., Chang, S. M., Berger, M. S., Solomon, D. A. 2025; 27 (1): 89-105

  Abstract

  Despite recent advances in the biology of IDH-wildtype glioblastoma, it remains a devastating disease with median survival of less than 2 years. However, the molecular underpinnings of the heterogeneous response to the current standard-of-care treatment regimen consisting of maximal safe resection, adjuvant radiation, and chemotherapy with temozolomide remain unknown.Comprehensive histopathologic, genomic, and epigenomic evaluation of paired initial and recurrent glioblastoma specimens from 106 patients was performed to investigate the molecular evolution and cellular phenotypes underlying differential treatment responses.While TERT promoter mutation and CDKN2A homozygous deletion were early events during gliomagenesis shared by initial and recurrent tumors, most other recurrent genetic alterations (eg, EGFR, PTEN, and NF1) were commonly private to initial or recurrent tumors indicating acquisition later during clonal evolution. Furthermore, glioblastomas exhibited heterogeneous epigenomic evolution with subsets becoming more globally hypermethylated, hypomethylated, or remaining stable. Glioblastoma that underwent sarcomatous transformation had shorter interval to recurrence and were significantly enriched in NF1, TP53, and RB1 alterations and the mesenchymal epigenetic class. Patients who developed somatic hypermutation following temozolomide treatment had significantly longer interval to disease recurrence and prolonged overall survival, and increased methylation at 4 specific CpG sites in the promoter region of MGMT was significantly associated with this development of hypermutation. Finally, an epigenomic evolution signature incorporating change in DNA methylation levels across 347 critical CpG sites was developed that significantly correlated with clinical outcomes.Glioblastoma undergoes heterogeneous genetic, epigenetic, and cellular evolution that underlies prognostically different treatment responses.

  View details for DOI 10.1093/neuonc/noae214

  View details for PubMedID 39560080

  View details for PubMedCentralID PMC11726253

• "De novo replication repair deficient glioblastoma, IDH-wildtype" is a distinct glioblastoma subtype in adults that may benefit from immune checkpoint blockade. Acta neuropathologica Hadad, S., Gupta, R., Oberheim Bush, N. A., Taylor, J. W., Villanueva-Meyer, J. E., Young, J. S., Wu, J., Ravindranathan, A., Zhang, Y., Warrier, G., McCoy, L., Shai, A., Pekmezci, M., Perry, A., Bollen, A. W., Phillips, J. J., Braunstein, S. E., Raleigh, D. R., Theodosopoulos, P., Aghi, M. K., Chang, E. F., Hervey-Jumper, S. L., Costello, J. F., de Groot, J., Butowski, N. A., Clarke, J. L., Chang, S. M., Berger, M. S., Molinaro, A. M., Solomon, D. A. 2023; 147 (1): 3

  Abstract

  Glioblastoma is a clinically and molecularly heterogeneous disease, and new predictive biomarkers are needed to identify those patients most likely to respond to specific treatments. Through prospective genomic profiling of 459 consecutive primary treatment-naïve IDH-wildtype glioblastomas in adults, we identified a unique subgroup (2%, 9/459) defined by somatic hypermutation and DNA replication repair deficiency due to biallelic inactivation of a canonical mismatch repair gene. The deleterious mutations in mismatch repair genes were often present in the germline in the heterozygous state with somatic inactivation of the remaining allele, consistent with glioblastomas arising due to underlying Lynch syndrome. A subset of tumors had accompanying proofreading domain mutations in the DNA polymerase POLE and resultant "ultrahypermutation". The median age at diagnosis was 50 years (range 27-78), compared with 63 years for the other 450 patients with conventional glioblastoma (p < 0.01). All tumors had histologic features of the giant cell variant of glioblastoma. They lacked EGFR amplification, lacked combined trisomy of chromosome 7 plus monosomy of chromosome 10, and only rarely had TERT promoter mutation or CDKN2A homozygous deletion, which are hallmarks of conventional IDH-wildtype glioblastoma. Instead, they harbored frequent inactivating mutations in TP53, NF1, PTEN, ATRX, and SETD2 and recurrent activating mutations in PDGFRA. DNA methylation profiling revealed they did not align with known reference adult glioblastoma methylation classes, but instead had unique globally hypomethylated epigenomes and mostly classified as "Diffuse pediatric-type high grade glioma, RTK1 subtype, subclass A". Five patients were treated with immune checkpoint blockade, four of whom survived greater than 3 years. The median overall survival was 36.8 months, compared to 15.5 months for the other 450 patients (p < 0.001). We conclude that "De novo replication repair deficient glioblastoma, IDH-wildtype" represents a biologically distinct subtype in the adult population that may benefit from prospective identification and treatment with immune checkpoint blockade.

  View details for DOI 10.1007/s00401-023-02654-1

  View details for PubMedID 38079020

  View details for PubMedCentralID PMC10713691

• Novel SOX10 indel mutations drive schwannomas through impaired transactivation of myelination gene programs. Neuro-oncology Williams, E. A., Ravindranathan, A., Gupta, R., Stevers, N. O., Suwala, A. K., Hong, C., Kim, S., Yuan, J. B., Wu, J., Barreto, J., Lucas, C. G., Chan, E., Pekmezci, M., LeBoit, P. E., Mully, T., Perry, A., Bollen, A., Van Ziffle, J., Devine, W. P., Reddy, A. T., Gupta, N., Basnet, K. M., Macaulay, R. J., Malafronte, P., Lee, H., Yong, W. H., Williams, K. J., Juratli, T. A., Mata, D. A., Huang, R. S., Hiemenz, M. C., Pavlick, D. C., Frampton, G. M., Janovitz, T., Ross, J. S., Chang, S. M., Berger, M. S., Jacques, L., Song, J. S., Costello, J. F., Solomon, D. A. 2023; 25 (12): 2221-2236

  Abstract

  Schwannomas are common peripheral nerve sheath tumors that can cause severe morbidity given their stereotypic intracranial and paraspinal locations. Similar to many solid tumors, schwannomas and other nerve sheath tumors are primarily thought to arise due to aberrant hyperactivation of the RAS growth factor signaling pathway. Here, we sought to further define the molecular pathogenesis of schwannomas.We performed comprehensive genomic profiling on a cohort of 96 human schwannomas, as well as DNA methylation profiling on a subset. Functional studies including RNA sequencing, chromatin immunoprecipitation-DNA sequencing, electrophoretic mobility shift assay, and luciferase reporter assays were performed in a fetal glial cell model following transduction with wildtype and tumor-derived mutant isoforms of SOX10.We identified that nearly one-third of sporadic schwannomas lack alterations in known nerve sheath tumor genes and instead harbor novel recurrent in-frame insertion/deletion mutations in SOX10, which encodes a transcription factor responsible for controlling Schwann cell differentiation and myelination. SOX10 indel mutations were highly enriched in schwannomas arising from nonvestibular cranial nerves (eg facial, trigeminal, vagus) and were absent from vestibular nerve schwannomas driven by NF2 mutation. Functional studies revealed these SOX10 indel mutations have retained DNA binding capacity but impaired transactivation of glial differentiation and myelination gene programs.We thus speculate that SOX10 indel mutations drive a unique subtype of schwannomas by impeding proper differentiation of immature Schwann cells.

  View details for DOI 10.1093/neuonc/noad121

  View details for PubMedID 37436963

  View details for PubMedCentralID PMC10708934

• Multiplatform molecular analyses refine classification of gliomas arising in patients with neurofibromatosis type 1. Acta neuropathologica Lucas, C. G., Sloan, E. A., Gupta, R., Wu, J., Pratt, D., Vasudevan, H. N., Ravindranathan, A., Barreto, J., Williams, E. A., Shai, A., Whipple, N. S., Bruggers, C. S., Maher, O., Nabors, B., Rodriguez, M., Samuel, D., Brown, M., Carmichael, J., Lu, R., Mirchia, K., Sullivan, D. V., Pekmezci, M., Tihan, T., Bollen, A. W., Perry, A., Banerjee, A., Mueller, S., Gupta, N., Hervey-Jumper, S. L., Oberheim Bush, N. A., Daras, M., Taylor, J. W., Butowski, N. A., de Groot, J., Clarke, J. L., Raleigh, D. R., Costello, J. F., Phillips, J. J., Reddy, A. T., Chang, S. M., Berger, M. S., Solomon, D. A. 2022; 144 (4): 747-765

  Abstract

  Gliomas arising in the setting of neurofibromatosis type 1 (NF1) are heterogeneous, occurring from childhood through adulthood, can be histologically low-grade or high-grade, and follow an indolent or aggressive clinical course. Comprehensive profiling of genetic alterations beyond NF1 inactivation and epigenetic classification of these tumors remain limited. Through next-generation sequencing, copy number analysis, and DNA methylation profiling of gliomas from 47 NF1 patients, we identified 2 molecular subgroups of NF1-associated gliomas. The first harbored biallelic NF1 inactivation only, occurred primarily during childhood, followed a more indolent clinical course, and had a unique epigenetic signature for which we propose the terminology "pilocytic astrocytoma, arising in the setting of NF1". The second subgroup harbored additional oncogenic alterations including CDKN2A homozygous deletion and ATRX mutation, occurred primarily during adulthood, followed a more aggressive clinical course, and was epigenetically diverse, with most tumors aligning with either high-grade astrocytoma with piloid features or various subclasses of IDH-wildtype glioblastoma. Several patients were treated with small molecule MEK inhibitors that resulted in stable disease or tumor regression when used as a single agent, but only in the context of those tumors with NF1 inactivation lacking additional oncogenic alterations. Together, these findings highlight recurrently altered pathways in NF1-associated gliomas and help inform targeted therapeutic strategies for this patient population.

  View details for DOI 10.1007/s00401-022-02478-5

  View details for PubMedID 35945463

  View details for PubMedCentralID PMC9468105

• Pediatric bithalamic gliomas have a distinct epigenetic signature and frequent EGFR exon 20 insertions resulting in potential sensitivity to targeted kinase inhibition. Acta neuropathologica Mondal, G., Lee, J. C., Ravindranathan, A., Villanueva-Meyer, J. E., Tran, Q. T., Allen, S. J., Barreto, J., Gupta, R., Doo, P., Van Ziffle, J., Onodera, C., Devine, P., Grenert, J. P., Samuel, D., Li, R., Metrock, L. K., Jin, L. W., Antony, R., Alashari, M., Cheshier, S., Whipple, N. S., Bruggers, C., Raffel, C., Gupta, N., Kline, C. N., Reddy, A., Banerjee, A., Hall, M. D., Mehta, M. P., Khatib, Z., Maher, O. M., Brathwaite, C., Pekmezci, M., Phillips, J. J., Bollen, A. W., Tihan, T., Lucas, J. T., Broniscer, A., Berger, M. S., Perry, A., Orr, B. A., Solomon, D. A. 2020; 139 (6): 1071-1088

  Abstract

  Brain tumors are the most common solid tumors of childhood, and the genetic drivers and optimal therapeutic strategies for many of the different subtypes remain unknown. Here, we identify that bithalamic gliomas harbor frequent mutations in the EGFR oncogene, only rare histone H3 mutation (in contrast to their unilateral counterparts), and a distinct genome-wide DNA methylation profile compared to all other glioma subtypes studied to date. These EGFR mutations are either small in-frame insertions within exon 20 (intracellular tyrosine kinase domain) or missense mutations within exon 7 (extracellular ligand-binding domain) that occur in the absence of accompanying gene amplification. We find these EGFR mutations are oncogenic in primary astrocyte models and confer sensitivity to specific tyrosine kinase inhibitors dependent on location within the kinase domain or extracellular domain. We initiated treatment with targeted kinase inhibitors in four children whose tumors harbor EGFR mutations with encouraging results. This study identifies a promising genomically-tailored therapeutic strategy for bithalamic gliomas, a lethal and genetically distinct brain tumor of childhood.

  View details for DOI 10.1007/s00401-020-02155-5

  View details for PubMedID 32303840

  View details for PubMedCentralID PMC7792550

• Recurrent KBTBD4 small in-frame insertions and absence of DROSHA deletion or DICER1 mutation differentiate pineal parenchymal tumor of intermediate differentiation (PPTID) from pineoblastoma. Acta neuropathologica Lee, J. C., Mazor, T., Lao, R., Wan, E., Diallo, A. B., Hill, N. S., Thangaraj, N., Wendelsdorf, K., Samuel, D., Kline, C. N., Banerjee, A., Auguste, K., Raffel, C., Gupta, N., Berger, M., Raleigh, D. R., Shai, A., Phillips, J. J., Bollen, A. W., Tihan, T., Perry, A., Costello, J., Solomon, D. A. 2019; 137 (5): 851-854

  View details for DOI 10.1007/s00401-019-01990-5

  View details for PubMedID 30877433

  View details for PubMedCentralID PMC6483828

• A requirement for STAG2 in replication fork progression creates a targetable synthetic lethality in cohesin-mutant cancers. Nature communications Mondal, G., Stevers, M., Goode, B., Ashworth, A., Solomon, D. A. 2019; 10 (1): 1686

  Abstract

  Cohesin is a multiprotein ring that is responsible for cohesion of sister chromatids and formation of DNA loops to regulate gene expression. Genomic analyses have identified that the cohesin subunit STAG2 is frequently inactivated by mutations in cancer. However, the reason STAG2 mutations are selected during tumorigenesis and strategies for therapeutically targeting mutant cancer cells are largely unknown. Here we show that STAG2 is essential for DNA replication fork progression, whereby STAG2 inactivation in non-transformed cells leads to replication fork stalling and collapse with disruption of interaction between the cohesin ring and the replication machinery as well as failure to establish SMC3 acetylation. As a consequence, STAG2 mutation confers synthetic lethality with DNA double-strand break repair genes and increased sensitivity to select cytotoxic chemotherapeutic agents and PARP or ATR inhibitors. These studies identify a critical role for STAG2 in replication fork procession and elucidate a potential therapeutic strategy for cohesin-mutant cancers.

  View details for DOI 10.1038/s41467-019-09659-z

  View details for PubMedID 30975996

  View details for PubMedCentralID PMC6459917

• The genetic landscape of gliomas arising after therapeutic radiation. Acta neuropathologica López, G. Y., Van Ziffle, J., Onodera, C., Grenert, J. P., Yeh, I., Bastian, B. C., Clarke, J., Oberheim Bush, N. A., Taylor, J., Chang, S., Butowski, N., Banerjee, A., Mueller, S., Kline, C., Torkildson, J., Samuel, D., Siongco, A., Raffel, C., Gupta, N., Kunwar, S., Mummaneni, P., Aghi, M., Theodosopoulos, P., Berger, M., Phillips, J. J., Pekmezci, M., Tihan, T., Bollen, A. W., Perry, A., Solomon, D. A. 2019; 137 (1): 139-150

  Abstract

  Radiotherapy improves survival for common childhood cancers such as medulloblastoma, leukemia, and germ cell tumors. Unfortunately, long-term survivors suffer sequelae that can include secondary neoplasia. Gliomas are common secondary neoplasms after cranial or craniospinal radiation, most often manifesting as high-grade astrocytomas with poor clinical outcomes. Here, we performed genetic profiling on a cohort of 12 gliomas arising after therapeutic radiation to determine their molecular pathogenesis and assess for differences in genomic signature compared to their spontaneous counterparts. We identified a high frequency of TP53 mutations, CDK4 amplification or CDKN2A homozygous deletion, and amplifications or rearrangements involving receptor tyrosine kinase and Ras-Raf-MAP kinase pathway genes including PDGFRA, MET, BRAF, and RRAS2. Notably, all tumors lacked alterations in IDH1, IDH2, H3F3A, HIST1H3B, HIST1H3C, TERT (including promoter region), and PTEN, which genetically define the major subtypes of diffuse gliomas in children and adults. All gliomas in this cohort had very low somatic mutation burden (less than three somatic single nucleotide variants or small indels per Mb). The ten high-grade gliomas demonstrated markedly aneuploid genomes, with significantly increased quantity of intrachromosomal copy number breakpoints and focal amplifications/homozygous deletions compared to spontaneous high-grade gliomas, likely as a result of DNA double-strand breaks induced by gamma radiation. Together, these findings demonstrate a distinct molecular pathogenesis of secondary gliomas arising after radiation therapy and identify a genomic signature that may aid in differentiating these tumors from their spontaneous counterparts.

  View details for DOI 10.1007/s00401-018-1906-z

  View details for PubMedID 30196423

  View details for PubMedCentralID PMC6589431

• Well-differentiated papillary mesothelioma of the peritoneum is genetically defined by mutually exclusive mutations in TRAF7 and CDC42. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc Stevers, M., Rabban, J. T., Garg, K., Van Ziffle, J., Onodera, C., Grenert, J. P., Yeh, I., Bastian, B. C., Zaloudek, C., Solomon, D. A. 2019; 32 (1): 88-99

  Abstract

  Well-differentiated papillary mesothelioma is an uncommon mesothelial neoplasm that most frequently arises in the peritoneal cavity of women of reproductive age. Whereas malignant mesothelioma is an aggressive tumor associated with poor outcome, well-differentiated papillary mesothelioma typically exhibits indolent behavior. However, histologically differentiating between these two entities can be challenging, necessitating the development of distinguishing biomarkers. While the genetic alterations that drive malignant mesothelioma have recently been determined, the molecular pathogenesis of well-differentiated papillary mesothelioma is unknown. Here we performed genomic profiling on a cohort of ten well-differentiated papillary mesothelioma of the peritoneum. We identified that all tumors harbored somatic missense mutations in either the TRAF7 or CDC42 genes, and lacked alterations involving BAP1, NF2, CDKN2A, DDX3X, SETD2, and ALK that are frequent in malignant mesothelioma. We recently identified that another mesothelial neoplasm, adenomatoid tumor of the genital tract, is genetically defined by somatic missense mutations in the TRAF7 gene, indicating a shared molecular pathogenesis between well-differentiated papillary mesothelioma and adenomatoid tumors. To the best of our knowledge, well-differentiated papillary mesothelioma is the first human tumor type found to harbor recurrent mutations in the CDC42 gene, which encodes a Rho family GTPase. Immunohistochemistry demonstrated intact BAP1 expression in all cases of well-differentiated papillary mesothelioma, indicating that this is a reliable marker for distinguishing well-differentiated papillary mesothelioma from malignant mesotheliomas that frequently display loss of expression. Additionally, all well-differentiated papillary mesothelioma demonstrated robust expression of L1 cell adhesion molecule (L1CAM), a marker of NF-kB pathway activation, similar to that observed in adenomatoid tumors. In contrast, we have previously shown that L1CAM staining is not observed in normal mesothelial cells and malignant mesotheliomas of the peritoneum. Together, these studies demonstrate that well-differentiated papillary mesothelioma is genetically defined by mutually exclusive mutations in TRAF7 and CDC42 that molecularly distinguish this entity from malignant mesothelioma.

  View details for DOI 10.1038/s41379-018-0127-2

  View details for PubMedID 30171198

  View details for PubMedCentralID PMC6309365

• Myxoid glioneuronal tumor of the septum pellucidum and lateral ventricle is defined by a recurrent PDGFRA p.K385 mutation and DNT-like methylation profile. Acta neuropathologica Solomon, D. A., Korshunov, A., Sill, M., Jones, D. T., Kool, M., Pfister, S. M., Fan, X., Bannykh, S., Hu, J., Danielpour, M., Li, R., Johnston, J., Cham, E., Cooney, T., Sun, P. P., Oberheim Bush, N. A., McDermott, M., Van Ziffle, J., Onodera, C., Grenert, J. P., Bastian, B. C., Villanueva-Meyer, J. E., Pekmezci, M., Bollen, A. W., Perry, A. 2018; 136 (2): 339-343

  View details for DOI 10.1007/s00401-018-1883-2

  View details for PubMedID 30006677

  View details for PubMedCentralID PMC7787982

• Adenomatoid tumors of the male and female genital tract are defined by TRAF7 mutations that drive aberrant NF-kB pathway activation. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc Goode, B., Joseph, N. M., Stevers, M., Van Ziffle, J., Onodera, C., Talevich, E., Grenert, J. P., Yeh, I., Bastian, B. C., Phillips, J. J., Garg, K., Rabban, J. T., Zaloudek, C., Solomon, D. A. 2018; 31 (4): 660-673

  Abstract

  Adenomatoid tumors are the most common neoplasm of the epididymis, and histologically similar adenomatoid tumors also commonly arise in the uterus and fallopian tube. To investigate the molecular pathogenesis of these tumors, we performed genomic profiling on a cohort of 31 adenomatoid tumors of the male and female genital tracts. We identified that all tumors harbored somatic missense mutations in the TRAF7 gene, which encodes an E3 ubiquitin ligase belonging to the family of tumor necrosis factor receptor-associated factors (TRAFs). These mutations all clustered into one of five recurrent hotspots within the WD40 repeat domains at the C-terminus of the protein. Functional studies in vitro revealed that expression of mutant but not wild-type TRAF7 led to increased phosphorylation of nuclear factor-kappa B (NF-kB) and increased expression of L1 cell adhesion molecule (L1CAM), a marker of NF-kB pathway activation. Immunohistochemistry demonstrated robust L1CAM expression in adenomatoid tumors that was absent in normal mesothelial cells, malignant peritoneal mesotheliomas and multilocular peritoneal inclusion cysts. Together, these studies demonstrate that adenomatoid tumors of the male and female genital tract are genetically defined by TRAF7 mutation that drives aberrant NF-kB pathway activation.

  View details for DOI 10.1038/modpathol.2017.153

  View details for PubMedID 29148537

  View details for PubMedCentralID PMC5906165

• Multinodular and vacuolating neuronal tumor of the cerebrum is a clonal neoplasm defined by genetic alterations that activate the MAP kinase signaling pathway. Acta neuropathologica Pekmezci, M., Stevers, M., Phillips, J. J., Van Ziffle, J., Bastian, B. C., Tsankova, N. M., Kleinschmidt-DeMasters, B. K., Rosenblum, M. K., Tihan, T., Perry, A., Solomon, D. A. 2018; 135 (3): 485-488

  View details for DOI 10.1007/s00401-018-1820-4

  View details for PubMedID 29428973

  View details for PubMedCentralID PMC6067952

• A recurrent kinase domain mutation in PRKCA defines chordoid glioma of the third ventricle. Nature communications Goode, B., Mondal, G., Hyun, M., Ruiz, D. G., Lin, Y. H., Van Ziffle, J., Joseph, N. M., Onodera, C., Talevich, E., Grenert, J. P., Hewedi, I. H., Snuderl, M., Brat, D. J., Kleinschmidt-DeMasters, B. K., Rodriguez, F. J., Louis, D. N., Yong, W. H., Lopes, M. B., Rosenblum, M. K., Butowski, N., Tihan, T., Bollen, A. W., Phillips, J. J., Wiita, A. P., Yeh, I., Jacobson, M. P., Bastian, B. C., Perry, A., Solomon, D. A. 2018; 9 (1): 810

  Abstract

  Chordoid glioma is a rare brain tumor thought to arise from specialized glial cells of the lamina terminalis along the anterior wall of the third ventricle. Despite being histologically low-grade, chordoid gliomas are often associated with poor outcome, as their stereotypic location in the third ventricle makes resection challenging and efficacious adjuvant therapies have not been developed. Here we performed genomic profiling on 13 chordoid gliomas and identified a recurrent D463H missense mutation in PRKCA in all tumors, which localizes in the kinase domain of the encoded protein kinase C alpha (PKCα). Expression of mutant PRKCA in immortalized human astrocytes led to increased phospho-ERK and anchorage-independent growth that could be blocked by MEK inhibition. These studies define PRKCA as a recurrently mutated oncogene in human cancer and identify a potential therapeutic vulnerability in this uncommon brain tumor.

  View details for DOI 10.1038/s41467-018-02826-8

  View details for PubMedID 29476136

  View details for PubMedCentralID PMC5824822

• Targeted next-generation sequencing of pediatric neuro-oncology patients improves diagnosis, identifies pathogenic germline mutations, and directs targeted therapy. Neuro-oncology Kline, C. N., Joseph, N. M., Grenert, J. P., van Ziffle, J., Talevich, E., Onodera, C., Aboian, M., Cha, S., Raleigh, D. R., Braunstein, S., Torkildson, J., Samuel, D., Bloomer, M., Campomanes, A. l., Banerjee, A., Butowski, N., Raffel, C., Tihan, T., Bollen, A. W., Phillips, J. J., Korn, W. M., Yeh, I., Bastian, B. C., Gupta, N., Mueller, S., Perry, A., Nicolaides, T., Solomon, D. A. 2017; 19 (5): 699-709

  Abstract

  Molecular profiling is revolutionizing cancer diagnostics and leading to personalized therapeutic approaches. Herein we describe our clinical experience performing targeted sequencing for 31 pediatric neuro-oncology patients.We sequenced 510 cancer-associated genes from tumor and peripheral blood to identify germline and somatic mutations, structural variants, and copy number changes.Genomic profiling was performed on 31 patients with tumors including 11 high-grade gliomas, 8 medulloblastomas, 6 low-grade gliomas, 1 embryonal tumor with multilayered rosettes, 1 pineoblastoma, 1 uveal ganglioneuroma, 1 choroid plexus carcinoma, 1 chordoma, and 1 high-grade neuroepithelial tumor. In 25 cases (81%), results impacted patient management by: (i) clarifying diagnosis, (ii) identifying pathogenic germline mutations, or (iii) detecting potentially targetable alterations. The pathologic diagnosis was amended after genomic profiling for 6 patients (19%), including a high-grade glioma to pilocytic astrocytoma, medulloblastoma to pineoblastoma, ependymoma to high-grade glioma, and medulloblastoma to CNS high-grade neuroepithelial tumor with BCOR alteration. Multiple patients had pathogenic germline mutations, many of which were previously unsuspected. Potentially targetable alterations were identified in 19 patients (61%). Additionally, novel likely pathogenic alterations were identified in 3 cases: an in-frame RAF1 fusion in a BRAF wild-type pleomorphic xanthoastrocytoma, an inactivating ASXL1 mutation in a histone H3 wild-type diffuse pontine glioma, and an in-frame deletion within exon 2 of MAP2K1 in a low-grade astrocytic neoplasm.Our experience demonstrates the significant impact of molecular profiling on diagnosis and treatment of pediatric brain tumors and confirms its feasibility for use at the time of diagnosis or recurrence.

  View details for DOI 10.1093/neuonc/now254

  View details for PubMedID 28453743

  View details for PubMedCentralID PMC5464451

• The genomic landscape of the Ewing Sarcoma family of tumors reveals recurrent STAG2 mutation. PLoS genetics Brohl, A. S., Solomon, D. A., Chang, W., Wang, J., Song, Y., Sindiri, S., Patidar, R., Hurd, L., Chen, L., Shern, J. F., Liao, H., Wen, X., Gerard, J., Kim, J. S., Lopez Guerrero, J. A., Machado, I., Wai, D. H., Picci, P., Triche, T., Horvai, A. E., Miettinen, M., Wei, J. S., Catchpool, D., Llombart-Bosch, A., Waldman, T., Khan, J. 2014; 10 (7): e1004475

  Abstract

  The Ewing sarcoma family of tumors (EFT) is a group of highly malignant small round blue cell tumors occurring in children and young adults. We report here the largest genomic survey to date of 101 EFT (65 tumors and 36 cell lines). Using a combination of whole genome sequencing and targeted sequencing approaches, we discover that EFT has a very low mutational burden (0.15 mutations/Mb) but frequent deleterious mutations in the cohesin complex subunit STAG2 (21.5% tumors, 44.4% cell lines), homozygous deletion of CDKN2A (13.8% and 50%) and mutations of TP53 (6.2% and 71.9%). We additionally note an increased prevalence of the BRCA2 K3326X polymorphism in EFT patient samples (7.3%) compared to population data (OR 7.1, p = 0.006). Using whole transcriptome sequencing, we find that 11% of tumors pathologically diagnosed as EFT lack a typical EWSR1 fusion oncogene and that these tumors do not have a characteristic Ewing sarcoma gene expression signature. We identify samples harboring novel fusion genes including FUS-NCATc2 and CIC-FOXO4 that may represent distinct small round blue cell tumor variants. In an independent EFT tissue microarray cohort, we show that STAG2 loss as detected by immunohistochemistry may be associated with more advanced disease (p = 0.15) and a modest decrease in overall survival (p = 0.10). These results significantly advance our understanding of the genomic and molecular underpinnings of Ewing sarcoma and provide a foundation towards further efforts to improve diagnosis, prognosis, and precision therapeutics testing.

  View details for DOI 10.1371/journal.pgen.1004475

  View details for PubMedID 25010205

  View details for PubMedCentralID PMC4091782

• Frequent truncating mutations of STAG2 in bladder cancer. Nature genetics Solomon, D. A., Kim, J. S., Bondaruk, J., Shariat, S. F., Wang, Z. F., Elkahloun, A. G., Ozawa, T., Gerard, J., Zhuang, D., Zhang, S., Navai, N., Siefker-Radtke, A., Phillips, J. J., Robinson, B. D., Rubin, M. A., Volkmer, B., Hautmann, R., Küfer, R., Hogendoorn, P. C., Netto, G., Theodorescu, D., James, C. D., Czerniak, B., Miettinen, M., Waldman, T. 2013; 45 (12): 1428-30

  Abstract

  Here we report the discovery of truncating mutations of the gene encoding the cohesin subunit STAG2, which regulates sister chromatid cohesion and segregation, in 36% of papillary non-invasive urothelial carcinomas and 16% of invasive urothelial carcinomas of the bladder. Our studies suggest that STAG2 has a role in controlling chromosome number but not the proliferation of bladder cancer cells. These findings identify STAG2 as one of the most commonly mutated genes in bladder cancer.

  View details for DOI 10.1038/ng.2800

  View details for PubMedID 24121789

  View details for PubMedCentralID PMC3875130

• Mutational inactivation of STAG2 causes aneuploidy in human cancer. Science (New York, N.Y.) Solomon, D. A., Kim, T., Diaz-Martinez, L. A., Fair, J., Elkahloun, A. G., Harris, B. T., Toretsky, J. A., Rosenberg, S. A., Shukla, N., Ladanyi, M., Samuels, Y., James, C. D., Yu, H., Kim, J. S., Waldman, T. 2011; 333 (6045): 1039-43

  Abstract

  Most cancer cells are characterized by aneuploidy, an abnormal number of chromosomes. We have identified a clue to the mechanistic origins of aneuploidy through integrative genomic analyses of human tumors. A diverse range of tumor types were found to harbor deletions or inactivating mutations of STAG2, a gene encoding a subunit of the cohesin complex, which regulates the separation of sister chromatids during cell division. Because STAG2 is on the X chromosome, its inactivation requires only a single mutational event. Studying a near-diploid human cell line with a stable karyotype, we found that targeted inactivation of STAG2 led to chromatid cohesion defects and aneuploidy, whereas in two aneuploid human glioblastoma cell lines, targeted correction of the endogenous mutant alleles of STAG2 led to enhanced chromosomal stability. Thus, genetic disruption of cohesin is a cause of aneuploidy in human cancer.

  View details for DOI 10.1126/science.1203619

  View details for PubMedID 21852505

  View details for PubMedCentralID PMC3374335

• Pharmacologic inhibition of cyclin-dependent kinases 4 and 6 arrests the growth of glioblastoma multiforme intracranial xenografts. Cancer research Michaud, K., Solomon, D. A., Oermann, E., Kim, J. S., Zhong, W. Z., Prados, M. D., Ozawa, T., James, C. D., Waldman, T. 2010; 70 (8): 3228-38

  Abstract

  Activation of cyclin-dependent kinases 4 and 6 (cdk4/6) occurs in the majority of glioblastoma multiforme (GBM) tumors, and represents a promising molecular target for the development of small molecule inhibitors. In the current study, we investigated the molecular determinants and in vivo response of diverse GBM cell lines and xenografts to PD-0332991, a cdk4/6-specific inhibitor. In vitro testing of PD-0332991 against a panel of GBM cell lines revealed a potent G(1) cell cycle arrest and induction of senescence in each of 16 retinoblastoma protein (Rb)-proficient cell lines regardless of other genetic lesions, whereas 5 cell lines with homozygous inactivation of Rb were completely resistant to treatment. Short hairpin RNA depletion of Rb expression conferred resistance of GBM cells to PD-0332991, further demonstrating a requirement of Rb for sensitivity to cdk4/6 inhibition. PD-0332991 was found to efficiently cross the blood-brain barrier and proved highly effective in suppressing the growth of intracranial GBM xenograft tumors, including those that had recurred after initial therapy with temozolomide. Remarkably, no mice receiving PD-0332991 died as a result of disease progression while on therapy. Additionally, the combination of PD-0332991 and radiation therapy resulted in significantly increased survival benefit compared with either therapy alone. In total, our results support clinical trial evaluation of PD-0332991 against newly diagnosed as well as recurrent GBM, and indicate that Rb status is the primary determinant of potential benefit from this therapy.

  View details for DOI 10.1158/0008-5472.CAN-09-4559

  View details for PubMedID 20354191

  View details for PubMedCentralID PMC2855904

• Identification of p18 INK4c as a tumor suppressor gene in glioblastoma multiforme. Cancer research Solomon, D. A., Kim, J. S., Jenkins, S., Ressom, H., Huang, M., Coppa, N., Mabanta, L., Bigner, D., Yan, H., Jean, W., Waldman, T. 2008; 68 (8): 2564-9

  Abstract

  Genomic alterations leading to aberrant activation of cyclin/cyclin-dependent kinase (cdk) complexes drive the pathogenesis of many common human tumor types. In the case of glioblastoma multiforme (GBM), these alterations are most commonly due to homozygous deletion of p16(INK4a) and less commonly due to genomic amplifications of individual genes encoding cyclins or cdks. Here, we describe deletion of the p18(INK4c) cdk inhibitor as a novel genetic alteration driving the pathogenesis of GBM. Deletions of p18(INK4c) often occurred in tumors also harboring homozygous deletions of p16(INK4a). Expression of p18(INK4c) was completely absent in 43% of GBM primary tumors studied by immunohistochemistry. Lentiviral reconstitution of p18(INK4c) expression at physiologic levels in p18(INK4c)-deficient but not p18(INK4c)-proficient GBM cells led to senescence-like G(1) cell cycle arrest. These studies identify p18(INK4c) as a GBM tumor suppressor gene, revealing an additional mechanism leading to aberrant activation of cyclin/cdk complexes in this terrible malignancy.

  View details for DOI 10.1158/0008-5472.CAN-07-6388

  View details for PubMedID 18381405

  View details for PubMedCentralID PMC4394609

• Cyclin D1 splice variants. Differential effects on localization, RB phosphorylation, and cellular transformation. The Journal of biological chemistry Solomon, D. A., Wang, Y., Fox, S. R., Lambeck, T. C., Giesting, S., Lan, Z., Senderowicz, A. M., Conti, C. J., Knudsen, E. S. 2003; 278 (32): 30339-47

  Abstract

  Cyclin D1 is a proto-oncogene that functions by inactivation of the retinoblastoma tumor suppressor protein, RB. A common polymorphism in the cyclin D1 gene is associated with the production of an alternate transcript of cyclin D1, termed cyclin D1b. Both the polymorphism and the variant transcript are associated with increased risk for multiple cancers and the severity of a given cancer; however, the underlying activities of cyclin D1b have not been elucidated relative to the canonical cyclin D1a. Because cyclin D1b does not possess the threonine 286 phosphorylation site required for nuclear export and regulated degradation, it has been hypothesized to encode a stable nuclear protein that would constitutively inactivate the RB pathway. Surprisingly, we find that cyclin D1b protein does not inappropriately accumulate in cells and exhibits stability comparable to cyclin D1a. As expected, the cyclin D1b protein was constitutively localized in the nucleus, whereas cyclin D1a was exported to the cytoplasm in S-phase. Despite enhanced nuclear localization, we find that cyclin D1b is a poor catalyst of RB phosphorylation/inactivation. However, cyclin D1b potently induced cellular transformation in contrast to cyclin D1a. In summary, we demonstrate that cyclin D1b specifically disrupts contact inhibition in a manner distinct from cyclin D1a. These data reveal novel roles for d-type cyclins in tumorigenesis.

  View details for DOI 10.1074/jbc.M303969200

  View details for PubMedID 12746453

• cIMPACT-NOW update 9: Recommendations on utilization of genome-wide DNA methylation profiling for central nervous system tumor diagnostics. Neuro-oncology advances Aldape, K., Capper, D., von Deimling, A., Giannini, C., Gilbert, M. R., Hawkins, C., Hench, J., Jacques, T. S., Jones, D., Louis, D. N., Mueller, S., Orr, B. A., Nasrallah, M., Pfister, S. M., Sahm, F., Snuderl, M., Solomon, D., Varlet, P., Wesseling, P. 2025; 7 (1): vdae228

  Abstract

  Genome-wide DNA methylation signatures correlate with and distinguish central nervous system (CNS) tumor types. Since the publication of the initial CNS tumor DNA methylation classifier in 2018, this platform has been increasingly used as a diagnostic tool for CNS tumors, with multiple studies showing the value and utility of DNA methylation-based classification of CNS tumors. A Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) Working Group was therefore convened to describe the current state of the field and to provide advice based on lessons learned to date. Here, we provide recommendations for the use of DNA methylation-based classification in CNS tumor diagnostics, emphasizing the attributes and limitations of the modality. We emphasize that the methylation classifier is one diagnostic tool to be used alongside previously established diagnostic tools in a fully integrated fashion. In addition, we provide examples of the inclusion of DNA methylation data within the layered diagnostic reporting format endorsed by the World Health Organization (WHO) and the International Collaboration on Cancer Reporting. We emphasize the need for backward compatibility of future platforms to enable accumulated data to be compatible with new versions of the array. Finally, we outline the specific connections between methylation classes and CNS WHO tumor types to aid in the interpretation of classifier results. It is hoped that this update will assist the neuro-oncology community in the interpretation of DNA methylation classifier results to facilitate the accurate diagnosis of CNS tumors and thereby help guide patient management.

  View details for DOI 10.1093/noajnl/vdae228

  View details for PubMedID 39902391

  View details for PubMedCentralID PMC11788596

• Molecular Testing for the World Health Organization Classification of Central Nervous System Tumors: A Review. JAMA oncology Horbinski, C., Solomon, D. A., Lukas, R. V., Packer, R. J., Brastianos, P., Wen, P. Y., Snuderl, M., Berger, M. S., Chang, S., Fouladi, M., Phillips, J. J., Nabors, B., Brat, D. J., Huse, J. T., Aldape, K., Sarkaria, J. N., Holdhoff, M., Burns, T. C., Peters, K. B., Mellinghoff, I. K., Arons, D., Galanis, E. 2024

  Abstract

  Molecular techniques, including next-generation sequencing, genomic copy number profiling, fusion transcript detection, and genomic DNA methylation arrays, are now indispensable tools for the workup of central nervous system (CNS) tumors. Yet there remains a great deal of heterogeneity in using such biomarker testing across institutions and hospital systems. This is in large part because there is a persistent reluctance among third-party payers to cover molecular testing. The objective of this Review is to describe why comprehensive molecular biomarker testing is now required for the accurate diagnosis and grading and prognostication of CNS tumors and, in so doing, to justify more widespread use by clinicians and coverage by third-party payers.The 5th edition of the World Health Organization (WHO) classification system for CNS tumors incorporates specific molecular signatures into the essential diagnostic criteria for most tumor entities. Many CNS tumor types cannot be reliably diagnosed according to current WHO guidelines without molecular testing. The National Comprehensive Cancer Network also incorporates molecular testing into their guidelines for CNS tumors. Both sets of guidelines are maximally effective if they are implemented routinely for all patients with CNS tumors. Moreover, the cost of these tests is less than 5% of the overall average cost of caring for patients with CNS tumors and consistently improves management. This includes more accurate diagnosis and prognostication, clinical trial eligibility, and prediction of response to specific treatments. Each major group of CNS tumors in the WHO classification is evaluated and how molecular diagnostics enhances patient care is described.Routine advanced multidimensional molecular profiling is now required to provide optimal standard of care for patients with CNS tumors.

  View details for DOI 10.1001/jamaoncol.2024.5506

  View details for PubMedID 39724142

• Identification of Genomic Biomarkers of Disease Progression and Survival in Primary CNS Lymphoma. Blood advances Geng, H., Mo, S. S., Chen, L., Ballapuram, A., Tsang, M., Lu, M., Rauschecker, A. M., Wen, K. W., Devine, W. P., Solomon, D. A., Rubenstein, J. L. 2024

  Abstract

  The determination of the genetic subtypes of primary CNS lymphoma (PCNSL) and their relationship to differential chemo-immunotherapeutic response has not been established. There is a particular need for genomic biomarkers that identify patients with newly-diagnosed PCNSL at high risk of early progression and death. We applied targeted next-generation sequencing for detection of recurrent single nucleotide variants, copy number alterations and zygosity abnormalities in diagnostic specimens from 78 PCNSL patients treated with a standard methotrexate-based regimen, to identify prognostically significant molecular subgroups. All patients received induction immunochemotherapy and 44 proceeded to dose-intensive consolidation. Genomic aberrations at four loci were associated with 91% of lymphoma progression events and all 15 deaths: (1) chromosome 6p copy-neutral loss of heterozygosity (CN-LOH) or focal homozygous deletion (HD) at 6p21.3, and mutations of tumor suppressor genes (2) BTG1, (3) ETV6 and (4) TP53. Cox regression multivariate analysis demonstrated a high risk of progression in patients with aberrations at these loci. Genomic aberrations at these loci were also associated with significantly shorter survival. Lower expression of HLA-DR was associated with 6p CN-LOH/6p21.3 HD and inferior prognosis. These genomic aberrations identify a high-risk molecular subgroup that may inform risk stratification in PCNSL. Further elucidation of the mechanisms of therapeutic resistance associated with the high-risk genetic phenotype is requisite to facilitate precision medicine and progress in therapy.

  View details for DOI 10.1182/bloodadvances.2024014460

  View details for PubMedID 39536287

• Toward standardized brain tumor tissue processing protocols in neuro-oncology: a perspective for gliomas and beyond. Frontiers in oncology Rodriguez, A., Ahluwalia, M. S., Bettegowda, C., Brem, H., Carter, B. S., Chang, S., Das, S., Eberhart, C., Garzon-Muvdi, T., Hadjipanayis, C. G., Hawkins, C., Jacques, T. S., Khalessi, A. A., McDermott, M. W., Mikkelsen, T., Orr, B. A., Phillips, J. J., Rosenblum, M., Shelton, W. J., Solomon, D. A., von Deimling, A., Woodworth, G. F., Rutka, J. T. 2024; 14: 1471257

  Abstract

  Implementation of standardized protocols in neurooncology during the surgical resection of brain tumors is needed to advance the clinical treatment paradigms that use tissue for diagnosis, prognosis, bio-banking, and treatment. Currently recommendations on intraoperative tissue procurement only exist for diffuse gliomas but management of other brain tumor subtypes can also benefit from these protocols. Fresh tissue from surgical resection can now be used for intraoperative diagnostics and functional precision medicine assays. A multidisciplinary neuro-oncology perspective is critical to develop the best avenues for practical standardization. This perspective from the multidisciplinary Oncology Tissue Advisory Board (OTAB) discusses current advances, future directions, and the imperative of adopting standardized protocols for diverse brain tumor entities. There is a growing need for consistent operating room practices to enhance patient care, streamline research efforts, and optimize outcomes.

  View details for DOI 10.3389/fonc.2024.1471257

  View details for PubMedID 39376983

  View details for PubMedCentralID PMC11456923

• The Chlamydia trachomatis Inc Tri1 interacts with TRAF7 to displace native TRAF7 interacting partners. Microbiology spectrum Herrera, C. M., McMahon, E., Swaney, D. L., Sherry, J., Pha, K., Adams-Boone, K., Johnson, J. R., Krogan, N. J., Stevers, M., Solomon, D., Elwell, C., Engel, J. 2024; 12 (7): e0045324

  Abstract

  Chlamydia trachomatis is the leading cause of bacterial sexually transmitted infections in the USA and of preventable blindness worldwide. This obligate intracellular pathogen replicates within a membrane-bound inclusion, but how it acquires nutrients from the host while avoiding detection by the innate immune system is incompletely understood. C. trachomatis accomplishes this in part through the translocation of a unique set of effectors into the inclusion membrane, the inclusion membrane proteins (Incs). Incs are ideally positioned at the host-pathogen interface to reprogram host signaling by redirecting proteins or organelles to the inclusion. Using a combination of co-affinity purification, immunofluorescence confocal imaging, and proteomics, we characterize the interaction between an early-expressed Inc of unknown function, Tri1, and tumor necrosis factor receptor-associated factor 7 (TRAF7). TRAF7 is a multi-domain protein with a RING finger ubiquitin ligase domain and a C-terminal WD40 domain. TRAF7 regulates several innate immune signaling pathways associated with C. trachomatis infection and is mutated in a subset of tumors. We demonstrate that Tri1 and TRAF7 specifically interact during infection and that TRAF7 is recruited to the inclusion. We further show that the predicted coiled-coil domain of Tri1 is necessary to interact with the TRAF7 WD40 domain. Finally, we demonstrate that Tri1 displaces the native TRAF7 binding partners, mitogen-activated protein kinase kinase kinase 2 (MEKK2), and MEKK3. Together, our results suggest that by displacing TRAF7 native binding partners, Tri1 has the capacity to alter TRAF7 signaling during C. trachomatis infection.IMPORTANCEChlamydia trachomatis is the leading cause of bacterial sexually transmitted infections in the USA and preventable blindness worldwide. Although easily treated with antibiotics, the vast majority of infections are asymptomatic and therefore go untreated, leading to infertility and blindness. This obligate intracellular pathogen evades the immune response, which contributes to these outcomes. Here, we characterize the interaction between a C. trachomatis-secreted effector, Tri1, and a host protein involved in innate immune signaling, TRAF7. We identified host proteins that bind to TRAF7 and demonstrated that Tri1 can displace these proteins upon binding to TRAF7. Remarkably, the region of TRAF7 to which these host proteins bind is often mutated in a subset of human tumors. Our work suggests a mechanism by which Tri1 may alter TRAF7 signaling and has implications not only in the pathogenesis of C. trachomatis infections but also in understanding the role of TRAF7 in cancer.

  View details for DOI 10.1128/spectrum.00453-24

  View details for PubMedID 38814079

  View details for PubMedCentralID PMC11218536

• Spatial genomic, biochemical and cellular mechanisms underlying meningioma heterogeneity and evolution. Nature genetics Lucas, C. G., Mirchia, K., Seo, K., Najem, H., Chen, W. C., Zakimi, N., Foster, K., Eaton, C. D., Cady, M. A., Choudhury, A., Liu, S. J., Phillips, J. J., Magill, S. T., Horbinski, C. M., Solomon, D. A., Perry, A., Vasudevan, H. N., Heimberger, A. B., Raleigh, D. R. 2024; 56 (6): 1121-1133

  Abstract

  Intratumor heterogeneity underlies cancer evolution and treatment resistance, but targetable mechanisms driving intratumor heterogeneity are poorly understood. Meningiomas are the most common primary intracranial tumors and are resistant to all medical therapies, and high-grade meningiomas have significant intratumor heterogeneity. Here we use spatial approaches to identify genomic, biochemical and cellular mechanisms linking intratumor heterogeneity to the molecular, temporal and spatial evolution of high-grade meningiomas. We show that divergent intratumor gene and protein expression programs distinguish high-grade meningiomas that are otherwise grouped together by current classification systems. Analyses of matched pairs of primary and recurrent meningiomas reveal spatial expansion of subclonal copy number variants associated with treatment resistance. Multiplexed sequential immunofluorescence and deconvolution of meningioma spatial transcriptomes using cell types from single-cell RNA sequencing show decreased immune infiltration, decreased MAPK signaling, increased PI3K-AKT signaling and increased cell proliferation, which are associated with meningioma recurrence. To translate these findings to preclinical models, we use CRISPR interference and lineage tracing approaches to identify combination therapies that target intratumor heterogeneity in meningioma cell co-cultures.

  View details for DOI 10.1038/s41588-024-01747-1

  View details for PubMedID 38760638

  View details for PubMedCentralID PMC11239374

• Whole tumor analysis reveals early origin of the TERT promoter mutation and intercellular heterogeneity in TERT expression. Neuro-oncology Appin, C. L., Hong, C., Suwala, A. K., Hilz, S., Mathur, R., Solomon, D. A., Smirnov, I. V., Stevers, N. O., Shai, A., Wang, A., Berger, M. S., Chang, S. M., Phillips, J. J., Costello, J. F. 2024; 26 (4): 640-652

  Abstract

  The TERT promoter mutation (TPM) is acquired in most IDH-wildtype glioblastomas (GBM) and IDH-mutant oligodendrogliomas (OD) enabling tumor cell immortality. Previous studies on TPM clonality show conflicting results. This study was performed to determine whether TPM is clonal on a tumor-wide scale.We investigated TPM clonality in relation to presumed early events in 19 IDH-wildtype GBM and 10 IDH-mutant OD using 3-dimensional comprehensive tumor sampling. We performed Sanger sequencing on 264 tumor samples and deep amplicon sequencing on 187 tumor samples. We obtained tumor purity and copy number estimates from whole exome sequencing. TERT expression was assessed by RNA-seq and RNAscope.We detected TPM in 100% of tumor samples with quantifiable tumor purity (219 samples). Variant allele frequencies (VAF) of TPM correlate positively with chromosome 10 loss in GBM (R = 0.85), IDH1 mutation in OD (R = 0.87), and with tumor purity (R = 0.91 for GBM; R = 0.90 for OD). In comparison, oncogene amplification was tumor-wide for MDM4- and most EGFR-amplified cases but heterogeneous for MYCN and PDGFRA, and strikingly high in low-purity samples. TPM VAF was moderately correlated with TERT expression (R = 0.52 for GBM; R = 0.65 for OD). TERT expression was detected in a subset of cells, solely in TPM-positive samples, including samples equivocal for tumor.On a tumor-wide scale, TPM is among the earliest events in glioma evolution. Intercellular heterogeneity of TERT expression, however, suggests dynamic regulation during tumor growth. TERT expression may be a tumor cell-specific biomarker.

  View details for DOI 10.1093/neuonc/noad231

  View details for PubMedID 38141254

  View details for PubMedCentralID PMC10995505

• Everolimus for Children With Recurrent or Progressive Low-Grade Glioma: Results From the Phase II PNOC001 Trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Haas-Kogan, D. A., Aboian, M. S., Minturn, J. E., Leary, S. E., Abdelbaki, M. S., Goldman, S., Elster, J. D., Kraya, A., Lueder, M. R., Ramakrishnan, D., von Reppert, M., Liu, K. X., Rokita, J. L., Resnick, A. C., Solomon, D. A., Phillips, J. J., Prados, M., Molinaro, A. M., Waszak, S. M., Mueller, S. 2024; 42 (4): 441-451

  Abstract

  The PNOC001 phase II single-arm trial sought to estimate progression-free survival (PFS) associated with everolimus therapy for progressive/recurrent pediatric low-grade glioma (pLGG) on the basis of phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway activation as measured by phosphorylated-ribosomal protein S6 and to identify prognostic and predictive biomarkers.Patients, age 3-21 years, with progressive/recurrent pLGG received everolimus orally, 5 mg/m2 once daily. Frequency of driver gene alterations was compared among independent pLGG cohorts of newly diagnosed and progressive/recurrent patients. PFS at 6 months (primary end point) and median PFS (secondary end point) were estimated for association with everolimus therapy.Between 2012 and 2019, 65 subjects with progressive/recurrent pLGG (median age, 9.6 years; range, 3.0-19.9; 46% female) were enrolled, with a median follow-up of 57.5 months. The 6-month PFS was 67.4% (95% CI, 60.0 to 80.0) and median PFS was 11.1 months (95% CI, 7.6 to 19.8). Hypertriglyceridemia was the most common grade ≥3 adverse event. PI3K/AKT/mTOR pathway activation did not correlate with clinical outcomes (6-month PFS, active 68.4% v nonactive 63.3%; median PFS, active 11.2 months v nonactive 11.1 months; P = .80). Rare/novel KIAA1549::BRAF fusion breakpoints were most frequent in supratentorial midline pilocytic astrocytomas, in patients with progressive/recurrent disease, and correlated with poor clinical outcomes (median PFS, rare/novel KIAA1549::BRAF fusion breakpoints 6.1 months v common KIAA1549::BRAF fusion breakpoints 16.7 months; P < .05). Multivariate analysis confirmed their independent risk factor status for disease progression in PNOC001 and other, independent cohorts. Additionally, rare pathogenic germline variants in homologous recombination genes were identified in 6.8% of PNOC001 patients.Everolimus is a well-tolerated therapy for progressive/recurrent pLGGs. Rare/novel KIAA1549::BRAF fusion breakpoints may define biomarkers for progressive disease and should be assessed in future clinical trials.

  View details for DOI 10.1200/JCO.23.01838

  View details for PubMedID 37978951

  View details for PubMedCentralID PMC10824388

• Glioblastoma evolution and heterogeneity from a 3D whole-tumor perspective. Cell Mathur, R., Wang, Q., Schupp, P. G., Nikolic, A., Hilz, S., Hong, C., Grishanina, N. R., Kwok, D., Stevers, N. O., Jin, Q., Youngblood, M. W., Stasiak, L. A., Hou, Y., Wang, J., Yamaguchi, T. N., Lafontaine, M., Shai, A., Smirnov, I. V., Solomon, D. A., Chang, S. M., Hervey-Jumper, S. L., Berger, M. S., Lupo, J. M., Okada, H., Phillips, J. J., Boutros, P. C., Gallo, M., Oldham, M. C., Yue, F., Costello, J. F. 2024; 187 (2): 446-463.e16

  Abstract

  Treatment failure for the lethal brain tumor glioblastoma (GBM) is attributed to intratumoral heterogeneity and tumor evolution. We utilized 3D neuronavigation during surgical resection to acquire samples representing the whole tumor mapped by 3D spatial coordinates. Integrative tissue and single-cell analysis revealed sources of genomic, epigenomic, and microenvironmental intratumoral heterogeneity and their spatial patterning. By distinguishing tumor-wide molecular features from those with regional specificity, we inferred GBM evolutionary trajectories from neurodevelopmental lineage origins and initiating events such as chromothripsis to emergence of genetic subclones and spatially restricted activation of differential tumor and microenvironmental programs in the core, periphery, and contrast-enhancing regions. Our work depicts GBM evolution and heterogeneity from a 3D whole-tumor perspective, highlights potential therapeutic targets that might circumvent heterogeneity-related failures, and establishes an interactive platform enabling 360° visualization and analysis of 3D spatial patterns for user-selected genes, programs, and other features across whole GBM tumors.

  View details for DOI 10.1016/j.cell.2023.12.013

  View details for PubMedID 38242087

  View details for PubMedCentralID PMC10832360

• Somatic mosaic SOX10 indel mutations underlie a form of segmental schwannomatosis. Acta neuropathologica Terry, M., Gupta, R., Ravindranathan, A., Wu, J., Chan, E., Bollen, A. W., Chang, S. M., Berger, M. S., Jacques, L., Solomon, D. A. 2023; 146 (6): 857-860

  View details for DOI 10.1007/s00401-023-02641-6

  View details for PubMedID 37821623

  View details for PubMedCentralID PMC10627975

• Targeted gene expression profiling predicts meningioma outcomes and radiotherapy responses. Nature medicine Chen, W. C., Choudhury, A., Youngblood, M. W., Polley, M. C., Lucas, C. G., Mirchia, K., Maas, S. L., Suwala, A. K., Won, M., Bayley, J. C., Harmanci, A. S., Harmanci, A. O., Klisch, T. J., Nguyen, M. P., Vasudevan, H. N., McCortney, K., Yu, T. J., Bhave, V., Lam, T. C., Pu, J. K., Li, L. F., Leung, G. K., Chan, J. W., Perlow, H. K., Palmer, J. D., Haberler, C., Berghoff, A. S., Preusser, M., Nicolaides, T. P., Mawrin, C., Agnihotri, S., Resnick, A., Rood, B. R., Chew, J., Young, J. S., Boreta, L., Braunstein, S. E., Schulte, J., Butowski, N., Santagata, S., Spetzler, D., Bush, N. A., Villanueva-Meyer, J. E., Chandler, J. P., Solomon, D. A., Rogers, C. L., Pugh, S. L., Mehta, M. P., Sneed, P. K., Berger, M. S., Horbinski, C. M., McDermott, M. W., Perry, A., Bi, W. L., Patel, A. J., Sahm, F., Magill, S. T., Raleigh, D. R. 2023; 29 (12): 3067-3076

  Abstract

  Surgery is the mainstay of treatment for meningioma, the most common primary intracranial tumor, but improvements in meningioma risk stratification are needed and indications for postoperative radiotherapy are controversial. Here we develop a targeted gene expression biomarker that predicts meningioma outcomes and radiotherapy responses. Using a discovery cohort of 173 meningiomas, we developed a 34-gene expression risk score and performed clinical and analytical validation of this biomarker on independent meningiomas from 12 institutions across 3 continents (N = 1,856), including 103 meningiomas from a prospective clinical trial. The gene expression biomarker improved discrimination of outcomes compared with all other systems tested (N = 9) in the clinical validation cohort for local recurrence (5-year area under the curve (AUC) 0.81) and overall survival (5-year AUC 0.80). The increase in AUC compared with the standard of care, World Health Organization 2021 grade, was 0.11 for local recurrence (95% confidence interval 0.07 to 0.17, P < 0.001). The gene expression biomarker identified meningiomas benefiting from postoperative radiotherapy (hazard ratio 0.54, 95% confidence interval 0.37 to 0.78, P = 0.0001) and suggested postoperative management could be refined for 29.8% of patients. In sum, our results identify a targeted gene expression biomarker that improves discrimination of meningioma outcomes, including prediction of postoperative radiotherapy responses.

  View details for DOI 10.1038/s41591-023-02586-z

  View details for PubMedID 37944590

  View details for PubMedCentralID PMC11073469

• Clinical, genomic, and epigenomic analyses of H3K27M-mutant diffuse midline glioma long-term survivors reveal a distinct group of tumors with MAPK pathway alterations. Acta neuropathologica Roberts, H. J., Ji, S., Picca, A., Sanson, M., Garcia, M., Snuderl, M., Schüller, U., Picart, T., Ducray, F., Green, A. L., Nakano, Y., Sturm, D., Abdullaev, Z., Aldape, K., Dang, D., Kumar-Sinha, C., Wu, Y. M., Robinson, D., Vo, J. N., Chinnaiyan, A. M., Cartaxo, R., Upadhyaya, S. A., Mody, R., Chiang, J., Baker, S., Solomon, D., Venneti, S., Pratt, D., Waszak, S. M., Koschmann, C. 2023; 146 (6): 849-852

  View details for DOI 10.1007/s00401-023-02640-7

  View details for PubMedID 37851269

  View details for PubMedCentralID PMC10627895

• Quantitative analysis of MGMT promoter methylation in glioblastoma suggests nonlinear prognostic effect. Neuro-oncology advances Gibson, D., Ravi, A., Rodriguez, E., Chang, S., Oberheim Bush, N., Taylor, J., Clarke, J., Solomon, D., Scheffler, A., Witte, J., Lambing, H., Okada, H., Berger, M., Chehab, F., Butowski, N. A. 2023; 5 (1): vdad115

  Abstract

  Epigenetic inhibition of the O6-methylguanine-DNA-methyltransferase (MGMT) gene has emerged as a clinically relevant prognostic marker in glioblastoma (GBM). Methylation of the MGMT promoter has been shown to increase chemotherapy efficacy. While traditionally reported as a binary marker, recent methodological advancements have led to quantitative methods of measuring promoter methylation, providing clearer insight into its functional relationship with survival.A CLIA assay and bisulfite sequencing was utilized to develop a quantitative, 17-point, MGMT promoter methylation index. GBMs of 240 newly diagnosed patients were sequenced and risk for mortality was assessed. Nonlinearities were captured by fitting splines to Cox proportional hazard models and plotting smoothed residuals. Covariates included age, Karnofsky performance status, IDH1 mutation, and extent of resection.Median follow-up time and progression-free survival were 16 and 9 months, respectively. A total of 176 subjects experienced death. A one-unit increase in promoter CpG methylation resulted in a 4% reduction in hazard (95% CI 0.93-0.99, P < .005). GBM patients with low levels of promoter methylation (1-6 CpG sites) fared markedly worse (HR = 1.62, 95% CI 1.03-2.54, P < .036) than individuals who were unmethylated. Subjects with medium levels of promoter methylation (7-12 sites) had the greatest reduction in hazard (HR = 0.48, 95% CI 0.29-0.80, P < .004), followed by individuals in the highest promoter methylation tertile (HR = 0.62, 95% CI 0.40-0.97, P < .035).Our findings suggest that the relationship between the extent of MGMT promoter methylation and survival in GBM may be nonlinear. These findings challenge the current understanding of MGMT and underlines the clinical importance of determining its prognostic utility. Potential limitations include censoring, sample size, and extraneous mutations.

  View details for DOI 10.1093/noajnl/vdad115

  View details for PubMedID 37899778

  View details for PubMedCentralID PMC10611422

• Loss of p16 expression is a sensitive marker of CDKN2A homozygous deletion in malignant meningiomas. Acta neuropathologica Tang, V., Lu, R., Mirchia, K., Van Ziffle, J., Devine, P., Lee, J., Phillips, J. J., Perry, A., Raleigh, D. R., Lucas, C. G., Solomon, D. A. 2023; 145 (4): 497-500

  View details for DOI 10.1007/s00401-023-02544-6

  View details for PubMedID 36723772

  View details for PubMedCentralID PMC10020299

• Molecular profiling identifies at least 3 distinct types of post-transplant lymphoproliferative disorder involving CNS. Blood advances Guney, E., Lucas, C. G., Singh, K., Pekmezci, M., Fernandez-Pol, S., Mirchia, K., Toland, A., Vogel, H., Bannykh, S. I., Schafernak, K. T., Alexandrescu, S., Mobley, B. C., Powell, S. Z., Davidson, C., Neltner, J., Boue, D. R., Hattab, E. M., Ferris, S. P., Ohgami, R. S., Rubenstein, J. L., Bollen, A. W., Tihan, T., Perry, A., Solomon, D. A., Wen, K. W. 2023

  View details for DOI 10.1182/bloodadvances.2022009521

  View details for PubMedID 36897259

• Patterns of Extraneural Metastases in Children With Ependymoma. Journal of pediatric hematology/oncology Chan, P. P., Whipple, N. S., Ramani, B., Solomon, D. A., Zhou, H., Linscott, L. L., Kestle, J. R., Bruggers, C. S. 2023; 45 (2): e272-e278

  Abstract

  Ependymomas account for 10% of all malignant pediatric central nervous system tumors. Standard therapy includes maximal safe surgical resection, followed by focal radiation. Despite the aggressive therapy, progression-free survival is poor. Most ependymoma relapses occur locally at the original tumor site. Extraneural presentations of ependymoma are extremely rare, and no standard of care treatment exists. We present a single-institution case series of 3 patients who experienced extraneural relapses of supratentorial ependymoma and describe their treatment and outcome. These cases of extraneural relapse highlight the possible modes of extraneural spread, including hematogenous, lymphatic, and microscopic seeding through surgical drains and shunts. In addition, they illustrate the increase in histologic grade and mutational burden that may occur at the time of relapse. These cases illustrate the role of aggressive, individualized treatment interventions using a combination of surgery, radiation, and chemotherapy.

  View details for DOI 10.1097/MPH.0000000000002587

  View details for PubMedID 36730676

• Amplification of the PLAG-family genes-PLAGL1 and PLAGL2-is a key feature of the novel tumor type CNS embryonal tumor with PLAGL amplification. Acta neuropathologica Keck, M. K., Sill, M., Wittmann, A., Joshi, P., Stichel, D., Beck, P., Okonechnikow, K., Sievers, P., Wefers, A. K., Roncaroli, F., Avula, S., McCabe, M. G., Hayden, J. T., Wesseling, P., Øra, I., Nistér, M., Kranendonk, M. E., Tops, B. B., Zapotocky, M., Zamecnik, J., Vasiljevic, A., Fenouil, T., Meyronet, D., von Hoff, K., Schüller, U., Loiseau, H., Figarella-Branger, D., Kramm, C. M., Sturm, D., Scheie, D., Rauramaa, T., Pesola, J., Gojo, J., Haberler, C., Brandner, S., Jacques, T., Sexton Oates, A., Saffery, R., Koscielniak, E., Baker, S. J., Yip, S., Snuderl, M., Ud Din, N., Samuel, D., Schramm, K., Blattner-Johnson, M., Selt, F., Ecker, J., Milde, T., von Deimling, A., Korshunov, A., Perry, A., Pfister, S. M., Sahm, F., Solomon, D. A., Jones, D. T. 2023; 145 (1): 49-69

  Abstract

  Pediatric central nervous system (CNS) tumors represent the most common cause of cancer-related death in children aged 0-14 years. They differ from their adult counterparts, showing extensive clinical and molecular heterogeneity as well as a challenging histopathological spectrum that often impairs accurate diagnosis. Here, we use DNA methylation-based CNS tumor classification in combination with copy number, RNA-seq, and ChIP-seq analysis to characterize a newly identified CNS tumor type. In addition, we report histology, patient characteristics, and survival data in this tumor type. We describe a biologically distinct pediatric CNS tumor type (n = 31 cases) that is characterized by focal high-level amplification and resultant overexpression of either PLAGL1 or PLAGL2, and an absence of recurrent genetic alterations characteristic of other pediatric CNS tumor types. Both genes act as transcription factors for a regulatory subset of imprinted genes (IGs), components of the Wnt/β-Catenin pathway, and the potential drug targets RET and CYP2W1, which are also specifically overexpressed in this tumor type. A derived PLAGL-specific gene expression signature indicates dysregulation of imprinting control and differentiation/development. These tumors occurred throughout the neuroaxis including the cerebral hemispheres, cerebellum, and brainstem, and were predominantly composed of primitive embryonal-like cells lacking robust expression of markers of glial or neuronal differentiation (e.g., GFAP, OLIG2, and synaptophysin). Tumors with PLAGL1 amplification were typically diagnosed during adolescence (median age 10.5 years), whereas those with PLAGL2 amplification were diagnosed during early childhood (median age 2 years). The 10-year overall survival was 66% for PLAGL1-amplified tumors, 25% for PLAGL2-amplified tumors, 18% for male patients, and 82% for female patients. In summary, we describe a new type of biologically distinct CNS tumor characterized by PLAGL1/2 amplification that occurs predominantly in infants and toddlers (PLAGL2) or adolescents (PLAGL1) which we consider best classified as a CNS embryonal tumor and which is associated with intermediate survival. The cell of origin and optimal treatment strategies remain to be defined.

  View details for DOI 10.1007/s00401-022-02516-2

  View details for PubMedID 36437415

  View details for PubMedCentralID PMC9807491

• A single-cell atlas of glioblastoma evolution under therapy reveals cell-intrinsic and cell-extrinsic therapeutic targets. Nature cancer Wang, L., Jung, J., Babikir, H., Shamardani, K., Jain, S., Feng, X., Gupta, N., Rosi, S., Chang, S., Raleigh, D., Solomon, D., Phillips, J. J., Diaz, A. A. 2022; 3 (12): 1534-1552

  Abstract

  Recent longitudinal studies of glioblastoma (GBM) have demonstrated a lack of apparent selection pressure for specific DNA mutations in recurrent disease. Single-cell lineage tracing has shown that GBM cells possess a high degree of plasticity. Together this suggests that phenotype switching, as opposed to genetic evolution, may be the escape mechanism that explains the failure of precision therapies to date. We profiled 86 primary-recurrent patient-matched paired GBM specimens with single-nucleus RNA, single-cell open-chromatin, DNA and spatial transcriptomic/proteomic assays. We found that recurrent GBMs are characterized by a shift to a mesenchymal phenotype. We show that the mesenchymal state is mediated by activator protein 1. Increased T-cell abundance at recurrence was prognostic and correlated with hypermutation status. We identified tumor-supportive networks of paracrine and autocrine signals between GBM cells, nonmalignant neuroglia and immune cells. We present cell-intrinsic and cell-extrinsic targets and a single-cell multiomics atlas of GBM under therapy.

  View details for DOI 10.1038/s43018-022-00475-x

  View details for PubMedID 36539501

  View details for PubMedCentralID PMC9767870

• Iris and Ciliary Body Melanocytomas Are Defined by Solitary GNAQ Mutation Without Additional Oncogenic Alterations. Ophthalmology Solomon, D. A., Ramani, B., Eiger-Moscovich, M., Milman, T., Uludag, G., Crawford, J. B., Phan, I., Char, D. H., Shields, C. L., Eagle, R. C., Bastian, B. C., Bloomer, M. M., Pekmezci, M. 2022; 129 (12): 1429-1439

  Abstract

  To analyze the genetic features of melanocytomas and melanomas of the anterior uvea and assess the value of molecular testing for diagnosis and prognostication.Retrospective case-control study.Patients with melanocytoma (n = 16) and melanoma (n = 19) of the anterior uvea.Targeted next-generation sequencing was performed on formalin-fixed, paraffin-embedded tumor tissue from anterior uveal melanocytic tumors and correlated with clinicopathologic features.Presence or absence of accompanying oncogenic alterations beyond GNAQ/GNA11 and their association with histologic features and local recurrence.Hotspot missense mutations in GNAQ/GNA11 were identified in 91% (32/35) of all cases. None of the melanocytomas with or without atypia demonstrated chromosomal imbalances or additional oncogenic variants beyond GNAQ mutation, and none recurred over a median follow-up of 36 months. Additional alterations identified in a subset of melanomas include mutations in BAP1 (n = 3), EIF1AX (n = 4), SRSF2 (n = 1), PTEN (n = 1), and EP300 (n = 1); monosomy 3p (n = 6); trisomy 6p (n = 3); trisomy 8q (n = 2); and an ultraviolet mutational signature (n = 5). Local recurrences were limited to melanomas, all of which demonstrated oncogenic alterations in addition to GNAQ/GNA11 (n = 5). A single melanoma harboring GNAQ and BAP1 mutations and monosomy 3 was the only tumor that metastasized.In this study, anterior segment uveal melanocytomas did not display oncogenic alterations beyond GNAQ/GNA11. Therefore, they are genetically similar to uveal nevi rather than uveal melanoma based on their molecular features known from the literature. Molecular testing can be performed on borderline cases to aid risk stratification and clinical management decisions.

  View details for DOI 10.1016/j.ophtha.2022.07.002

  View details for PubMedID 35835335

• EANO - EURACAN - SNO Guidelines on circumscribed astrocytic gliomas, glioneuronal, and neuronal tumors. Neuro-oncology Rudà, R., Capper, D., Waldman, A. D., Pallud, J., Minniti, G., Kaley, T. J., Bouffet, E., Tabatabai, G., Aronica, E., Jakola, A. S., Pfister, S. M., Schiff, D., Lassman, A. B., Solomon, D. A., Soffietti, R., Weller, M., Preusser, M., Idbaih, A., Wen, P. Y., van den Bent, M. J. 2022; 24 (12): 2015-2034

  Abstract

  In the new WHO 2021 Classification of CNS Tumors the chapter "Circumscribed astrocytic gliomas, glioneuronal and neuronal tumors" encompasses several different rare tumor entities, which occur more frequently in children, adolescents, and young adults. The Task Force has reviewed the evidence of diagnostic and therapeutic interventions, which is low particularly for adult patients, and draw recommendations accordingly. Tumor diagnosis, based on WHO 2021, is primarily performed using conventional histological techniques; however, a molecular workup is important for differential diagnosis, in particular, DNA methylation profiling for the definitive classification of histologically unresolved cases. Molecular factors are increasing of prognostic and predictive importance. MRI finding are non-specific, but for some tumors are characteristic and suggestive. Gross total resection, when feasible, is the most important treatment in terms of prolonging survival and achieving long-term seizure control. Conformal radiotherapy should be considered in grade 3 and incompletely resected grade 2 tumors. In recurrent tumors reoperation and radiotherapy, including stereotactic radiotherapy, can be useful. Targeted therapies may be used in selected patients: BRAF and MEK inhibitors in pilocytic astrocytomas, pleomorphic xanthoastrocytomas, and gangliogliomas when BRAF altered, and mTOR inhibitor everolimus in subependymal giant cells astrocytomas. Sequencing to identify molecular targets is advocated for diagnostic clarification and to direct potential targeted therapies.

  View details for DOI 10.1093/neuonc/noac188

  View details for PubMedID 35908833

  View details for PubMedCentralID PMC9713532

• Expanded analysis of high-grade astrocytoma with piloid features identifies an epigenetically and clinically distinct subtype associated with neurofibromatosis type 1. Acta neuropathologica Cimino, P. J., Ketchum, C., Turakulov, R., Singh, O., Abdullaev, Z., Giannini, C., Pytel, P., Lopez, G. Y., Colman, H., Nasrallah, M. P., Santi, M., Fernandes, I. L., Nirschl, J., Dahiya, S., Neill, S., Solomon, D., Perez, E., Capper, D., Mani, H., Caccamo, D., Ball, M., Badruddoja, M., Chkheidze, R., Camelo-Piragua, S., Fullmer, J., Alexandrescu, S., Yeaney, G., Eberhart, C., Martinez-Lage, M., Chen, J., Zach, L., Kleinschmidt-DeMasters, B. K., Hefti, M., Lopes, M., Nuechterlein, N., Horbinski, C., Rodriguez, F. J., Quezado, M., Pratt, D., Aldape, K. 2022

  Abstract

  High-grade astrocytoma with piloid features (HGAP) is a recently recognized glioma type whose classification is dependent on its global epigenetic signature. HGAP is characterized by alterations in the mitogen-activated protein kinase (MAPK) pathway, often co-occurring with CDKN2A/B homozygous deletion and/or ATRX mutation. Experience with HGAP is limited and to better understand this tumor type, we evaluated an expanded cohort of patients (n=144) with these tumors, as defined by DNA methylation array testing, with a subset additionally evaluated by next-generation sequencing (NGS). Among evaluable cases, we confirmed the high prevalence CDKN2A/B homozygous deletion, and/or ATRX mutations/loss in this tumor type, along with a subset showing NF1 alterations. Five of 93 (5.4%) cases sequenced harbored TP53 mutations and RNA fusion analysis identified a single tumor containing an NTRK2 gene fusion, neither of which have been previously reported in HGAP. Clustering analysis revealed the presence of three distinct HGAP subtypes (or groups=g) based on whole-genome DNA methylation patterns, which we provisionally designated as gNF1 (n=18), g1 (n=72), and g2 (n=54) (median ages 43.5years, 47years, and 32years, respectively). Subtype gNF1 is notable for enrichment with patients with Neurofibromatosis Type 1 (33.3%, p=0.0008), confinement to the posterior fossa, hypermethylation in the NF1 enhancer region, a trend towards decreased progression-free survival (p=0.0579), RNA processing pathway dysregulation, and elevated non-neoplastic glia and neuron cell content (p<0.0001 and p<0.0001, respectively). Overall, our expanded cohort broadens the genetic, epigenetic, and clinical phenotype of HGAP and provides evidence for distinct epigenetic subtypes in this tumor type.

  View details for DOI 10.1007/s00401-022-02513-5

  View details for PubMedID 36271929

• Prospective genomically guided identification of "early/evolving" and "undersampled" IDH-wildtype glioblastoma leads to improved clinical outcomes. Neuro-oncology Zhang, Y., Lucas, C. G., Young, J. S., Morshed, R. A., McCoy, L., Oberheim Bush, N. A., Taylor, J. W., Daras, M., Butowski, N. A., Villanueva-Meyer, J. E., Cha, S., Wrensch, M., Wiencke, J. K., Lee, J. C., Pekmezci, M., Phillips, J. J., Perry, A., Bollen, A. W., Aghi, M. K., Theodosopoulos, P., Chang, E. F., Hervey-Jumper, S. L., Berger, M. S., Clarke, J. L., Chang, S. M., Molinaro, A. M., Solomon, D. A. 2022; 24 (10): 1749-1762

  Abstract

  Genomic profiling studies of diffuse gliomas have led to new improved classification schemes that better predict patient outcomes compared to conventional histomorphology alone. One example is the recognition that patients with IDH-wildtype diffuse astrocytic gliomas demonstrating lower-grade histologic features but genomic and/or epigenomic profile characteristic of glioblastoma typically have poor outcomes similar to patients with histologically diagnosed glioblastoma. Here we sought to determine the clinical impact of prospective genomic profiling for these IDH-wildtype diffuse astrocytic gliomas lacking high-grade histologic features but with molecular profile of glioblastoma.Clinical management and outcomes were analyzed for 38 consecutive adult patients with IDH-wildtype diffuse astrocytic gliomas lacking necrosis or microvascular proliferation on histologic examination that were genomically profiled on a prospective clinical basis revealing criteria for an integrated diagnosis of "diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV" per cIMPACT-NOW criteria.We identified that this diagnosis consists of two divergent clinical scenarios based on integration of radiologic, histologic, and genomic features that we term "early/evolving" and "undersampled" glioblastoma, IDH-wildtype. We found that prospective genomically guided identification of early/evolving and undersampled IDH-wildtype glioblastoma resulted in more aggressive patient management and improved clinical outcomes compared to a biologically matched historical control patient cohort receiving standard-of-care therapy based on histomorphologic diagnosis alone.These results support routine use of genomic and/or epigenomic profiling to accurately classify glial neoplasms, as these assays not only improve diagnostic classification but critically lead to more appropriate patient management that can improve clinical outcomes.

  View details for DOI 10.1093/neuonc/noac089

  View details for PubMedID 35395677

  View details for PubMedCentralID PMC9527525

• Conserved features of TERT promoter duplications reveal an activation mechanism that mimics hotspot mutations in cancer. Nature communications Barger, C. J., Suwala, A. K., Soczek, K. M., Wang, A. S., Kim, M. Y., Hong, C., Doudna, J. A., Chang, S. M., Phillips, J. J., Solomon, D. A., Costello, J. F. 2022; 13 (1): 5430

  Abstract

  Mutations in the TERT promoter represent the genetic underpinnings of tumor cell immortality. Beyond the two most common point mutations, which selectively recruit the ETS factor GABP to activate TERT, the significance of other variants is unknown. In seven cancer types, we identify duplications of wildtype sequence within the core promoter region of TERT that have strikingly similar features including an ETS motif, the duplication length and insertion site. The duplications recruit a GABP tetramer by virtue of the native ETS motif and its precisely spaced duplicated counterpart, activate the promoter and are clonal in a TERT expressing multifocal glioblastoma. We conclude that recurrent TERT promoter duplications are functionally and mechanistically equivalent to the hotspot mutations that confer tumor cell immortality. The shared mechanism of these divergent somatic genetic alterations suggests a strong selective pressure for recruitment of the GABP tetramer to activate TERT.

  View details for DOI 10.1038/s41467-022-33099-x

  View details for PubMedID 36114166

  View details for PubMedCentralID PMC9481613

• PI3K/AKT/mTOR signaling pathway activity in IDH-mutant diffuse glioma and clinical implications. Neuro-oncology Mohamed, E., Kumar, A., Zhang, Y., Wang, A. S., Chen, K., Lim, Y., Shai, A., Taylor, J. W., Clarke, J., Hilz, S., Berger, M. S., Solomon, D. A., Costello, J. F., Molinaro, A. M., Phillips, J. J. 2022; 24 (9): 1471-1481

  Abstract

  IDH-mutant diffuse gliomas are heterogeneous, and improved methods for optimal patient therapeutic stratification are needed. PI3K/AKT/mTOR signaling activity can drive disease progression and potential therapeutic inhibitors of the pathway are available. Yet, the prevalence of PI3K/AKT/mTOR signaling pathway activity in IDH-mutant glioma is unclear and few robust strategies to assess activity in clinical samples exist.PI3K/AKT/mTOR signaling pathway activity was evaluated in a retrospective cohort of 132 IDH-mutant diffuse glioma (91 astrocytoma and 41 oligodendroglioma, 1p/19q-codeleted) through quantitative multiplex immunoprofiling using phospho-specific antibodies for PI3K/AKT/mTOR pathway members, PRAS40, RPS6, and 4EBP1, and tumor-specific anti-IDH1 R132H. Expression levels were correlated with genomic evaluation of pathway intrinsic genes and univariate and multivariate Cox proportional hazard regression models were used to evaluate the relationship with outcome.Tumor-specific expression of p-PRAS40, p-RPS6, and p-4EBP1 was common in IDH-mutant diffuse glioma and increased with CNS WHO grade from 2 to 3. Genomic analysis predicted pathway activity in 21.7% (13/60) while protein evaluation identified active PI3K/AKT/mTOR signaling in 56.6% (34/60). Comparison of expression in male versus female patients suggested sexual dimorphism. Of particular interest, when adjusting for clinical prognostic factors, the level of phosphorylation of RPS6 was strongly associated with PFS (P < .005). Phosphorylation levels of both PRAS40 and RPS6 showed an association with PFS in univariate analysis.Our study emphasizes the value of proteomic assessment of signaling pathway activity in tumors as a means to identify relevant oncogenic pathways and potentially as a biomarker for identifying aggressive disease.

  View details for DOI 10.1093/neuonc/noac064

  View details for PubMedID 35287169

  View details for PubMedCentralID PMC9435510

• Intratumor and informatic heterogeneity influence meningioma molecular classification. Acta neuropathologica Vasudevan, H. N., Choudhury, A., Hilz, S., Villanueva-Meyer, J. E., Chen, W. C., Lucas, C. G., Braunstein, S. E., Oberheim Bush, N. A., Butowski, N., Pekmezci, M., McDermott, M. W., Perry, A., Solomon, D. A., Magill, S. T., Raleigh, D. R. 2022; 144 (3): 579-583

  View details for DOI 10.1007/s00401-022-02455-y

  View details for PubMedID 35759011

  View details for PubMedCentralID PMC9618384

• Recurrent ACVR1 mutations in posterior fossa ependymoma. Acta neuropathologica Pratt, D., Lucas, C. G., Selvam, P. P., Abdullaev, Z., Ketchum, C., Quezado, M., Armstrong, T. S., Gilbert, M. R., Papanicolau-Sengos, A., Raffeld, M., Choo-Wosoba, H., Chan, P., Whipple, N., Nasrallah, M., Santi, M., Ramaswamy, V., Giannini, C., Ritzmann, T. A., Grundy, R. G., Burford, A., Jones, C., Hawkins, C., Venneti, S., Solomon, D. A., Aldape, K. 2022; 144 (2): 373-376

  View details for DOI 10.1007/s00401-022-02435-2

  View details for PubMedID 35587280

  View details for PubMedCentralID 3997489

• Targeted Next-Generation Sequencing Reveals Divergent Clonal Evolution in Components of Composite Pleomorphic Xanthoastrocytoma-Ganglioglioma. Journal of neuropathology and experimental neurology Lucas, C. G., Davidson, C. J., Alashari, M., Putnam, A. R., Whipple, N. S., Bruggers, C. S., Mendez, J. S., Cheshier, S. H., Walker, J. B., Ramani, B., Cadwell, C. R., Sullivan, D. V., Lu, R., Mirchia, K., Van Ziffle, J., Devine, P., Goldschmidt, E., Hervey-Jumper, S. L., Gupta, N., Oberheim Bush, N. A., Raleigh, D. R., Bollen, A., Tihan, T., Pekmezci, M., Solomon, D. A., Phillips, J. J., Perry, A. 2022; 81 (8): 650-657

  Abstract

  Composite pleomorphic xanthoastrocytoma-ganglioglioma (PXA-GG) is an extremely rare central nervous system neoplasm with 2 distinct but intermingled components. Whether this tumor represents a "collision tumor" of separate neoplasms or a monoclonal neoplasm with divergent evolution is poorly understood. Clinicopathologic studies and capture-based next generation sequencing were performed on extracted DNA from all available PXA-GG at 2 medical centers. Five PXA-GG were diagnosed in 1 male and 4 female patients ranging from 13 to 25 years in age. Four arose within the cerebral hemispheres; 1 presented in the cerebellar vermis. DNA was sufficient for analysis in 4 PXA components and 3 GG components. Four paired PXA and GG components harbored BRAF p.V600E hotspot mutations. The 4 sequenced PXA components demonstrated CDKN2A homozygous deletion by sequencing with loss of p16 (protein product of CDKN2A) expression by immunohistochemistry, which was intact in all assessed GG components. The PXA components also demonstrated more frequent copy number alterations relative to paired GG components. In one PXA-GG, shared chromosomal copy number alterations were identified in both components. Our findings support divergent evolution of the PXA and GG components from a common BRAF p.V600E-mutant precursor lesion, with additional acquisition of CDKN2A homozygous deletion in the PXA component as is typically seen in conventional PXA.

  View details for DOI 10.1093/jnen/nlac044

  View details for PubMedID 35703914

  View details for PubMedCentralID PMC9297094

• Intracranial mesenchymal tumors with FET-CREB fusion are composed of at least two epigenetic subgroups distinct from meningioma and extracranial sarcomas. Brain pathology (Zurich, Switzerland) Sloan, E. A., Gupta, R., Koelsche, C., Chiang, J., Villanueva-Meyer, J. E., Alexandrescu, S., Eschbacher, J. M., Wang, W., Mafra, M., Ud Din, N., Carr-Boyd, E., Watson, M., Punsoni, M., Oviedo, A., Gilani, A., Kleinschmidt-DeMasters, B. K., Coss, D. J., Lopes, M. B., Reddy, A., Mueller, S., Cho, S. J., Horvai, A. E., Lee, J. C., Pekmezci, M., Tihan, T., Bollen, A. W., Rodriguez, F. J., Ellison, D. W., Perry, A., von Deimling, A., Chang, S. M., Berger, M. S., Solomon, D. A. 2022; 32 (4): e13037

  Abstract

  'Intracranial mesenchymal tumor, FET-CREB fusion-positive' occurs primarily in children and young adults and has previously been termed intracranial angiomatoid fibrous histiocytoma (AFH) or intracranial myxoid mesenchymal tumor (IMMT). Here we performed genome-wide DNA methylation array profiling of 20 primary intracranial mesenchymal tumors with FET-CREB fusion to further study their ontology. These tumors resolved into two distinct epigenetic subgroups that were both divergent from all other analyzed intracranial neoplasms and soft tissue sarcomas, including meningioma, clear cell sarcoma of soft tissue (CCS), and AFH of extracranial soft tissue. The first subgroup (Group A, 16 tumors) clustered nearest to but independent of solitary fibrous tumor and AFH of extracranial soft tissue, whereas the second epigenetic subgroup (Group B, 4 tumors) clustered nearest to but independent of CCS and also lacked expression of melanocytic markers (HMB45, Melan A, or MITF) characteristic of CCS. Group A tumors most often occurred in adolescence or early adulthood, arose throughout the neuroaxis, and contained mostly EWSR1-ATF1 and EWSR1-CREB1 fusions. Group B tumors arose most often in early childhood, were located along the cerebral convexities or spinal cord, and demonstrated an enrichment for tumors with CREM as the fusion partner (either EWSR1-CREM or FUS-CREM). Group A tumors more often demonstrated stellate/spindle cell morphology and hemangioma-like vasculature, whereas Group B tumors more often demonstrated round cell or epithelioid/rhabdoid morphology without hemangioma-like vasculature, although robust comparison of these clinical and histologic features requires future study. Patients with Group B tumors had inferior progression-free survival relative to Group A tumors (median 4.5 vs. 49 months, p = 0.001). Together, these findings confirm that intracranial AFH-like neoplasms and IMMT represent histologic variants of a single tumor type ('intracranial mesenchymal tumor, FET-CREB fusion-positive') that is distinct from meningioma and extracranial sarcomas. Additionally, epigenomic evaluation may provide important prognostic subtyping for this unique tumor entity.

  View details for DOI 10.1111/bpa.13037

  View details for PubMedID 34821426

  View details for PubMedCentralID PMC9245938

• CXCL14 Promotes a Robust Brain Tumor-Associated Immune Response in Glioma. Clinical cancer research : an official journal of the American Association for Cancer Research Kumar, A., Mohamed, E., Tong, S., Chen, K., Mukherjee, J., Lim, Y., Wong, C. M., Boosalis, Z., Shai, A., Pieper, R. O., Gupta, N., Perry, A., Bollen, A. W., Molinaro, A. M., Solomon, D. A., Shieh, J. T., Phillips, J. J. 2022; 28 (13): 2898-2910

  Abstract

  The immunosuppressive tumor microenvironment present in the majority of diffuse glioma limits therapeutic response to immunotherapy. As the determinants of the glioma-associated immune response are relatively poorly understood, the study of glioma with more robust tumor-associated immune responses may be particularly useful to identify novel immunomodulatory factors that can promote T-cell effector function in glioma.We used multiplex immune-profiling, proteomic profiling, and gene expression analysis to define the tumor-associated immune response in two molecular subtypes of glioma and identify factors that may modulate this response. We then used patient-derived glioma cultures and an immunocompetent murine model for malignant glioma to analyze the ability of tumor-intrinsic factors to promote a CD8+ T-cell response.As compared with isocitrate dehydrogenase (IDH)-mutant astrocytoma, MAPK-activated pleomorphic xanthoastrocytoma (PXA) harbored increased numbers of activated cytotoxic CD8+ T cells and Iba1+ microglia/macrophages, increased MHC class I expression, enrichment of genes associated with antigen presentation and processing, and increased tumor cell secretion of the chemokine CXCL14. CXCL14 promoted activated CD8+ T-cell chemotaxis in vitro, recruited tumor-infiltrating CD8+ T cells in vivo, and prolonged overall survival in a cytotoxic T-cell-dependent manner. The immunomodulatory molecule B7-H3 was also highly expressed in PXA.We identify the MAPK-activated lower grade astrocytoma PXA as having an immune-rich tumor microenvironment and suggest this tumor may be particularly vulnerable to immunotherapeutic modulation. We also identify CXCL14 as an important determinant of the glioma-associated immune microenvironment, sufficient to promote an antitumor CD8+ T-cell response.

  View details for DOI 10.1158/1078-0432.CCR-21-2830

  View details for PubMedID 35511927

  View details for PubMedCentralID PMC9250623

• A genetically distinct pediatric subtype of primary CNS large B-cell lymphoma is associated with favorable clinical outcome. Blood advances Güney, E., Lucas, C. G., Qi, Z., Yu, J., Zhang, R., Ohgami, R. S., Rubenstein, J. L., Boué, D. R., Schafernak, K., Wertheim, G. B., Dahiya, S., Giulino-Roth, L., Attarbaschi, A., Barth, M. J., Kothari, S., Abla, O., Cohen, A. L., Mendez, J. S., Bollen, A., Perry, A., Tihan, T., Pekmezci, M., Solomon, D. A., Wen, K. W. 2022; 6 (10): 3189-3193

  View details for DOI 10.1182/bloodadvances.2021006018

  View details for PubMedID 35157770

  View details for PubMedCentralID PMC9131901

• Meningioma DNA methylation groups identify biological drivers and therapeutic vulnerabilities. Nature genetics Choudhury, A., Magill, S. T., Eaton, C. D., Prager, B. C., Chen, W. C., Cady, M. A., Seo, K., Lucas, C. G., Casey-Clyde, T. J., Vasudevan, H. N., Liu, S. J., Villanueva-Meyer, J. E., Lam, T. C., Pu, J. K., Li, L. F., Leung, G. K., Swaney, D. L., Zhang, M. Y., Chan, J. W., Qiu, Z., Martin, M. V., Susko, M. S., Braunstein, S. E., Bush, N. A., Schulte, J. D., Butowski, N., Sneed, P. K., Berger, M. S., Krogan, N. J., Perry, A., Phillips, J. J., Solomon, D. A., Costello, J. F., McDermott, M. W., Rich, J. N., Raleigh, D. R. 2022; 54 (5): 649-659

  Abstract

  Meningiomas are the most common primary intracranial tumors. There are no effective medical therapies for meningioma patients, and new treatments have been encumbered by limited understanding of meningioma biology. Here, we use DNA methylation profiling on 565 meningiomas integrated with genetic, transcriptomic, biochemical, proteomic and single-cell approaches to show meningiomas are composed of three DNA methylation groups with distinct clinical outcomes, biological drivers and therapeutic vulnerabilities. Merlin-intact meningiomas (34%) have the best outcomes and are distinguished by NF2/Merlin regulation of susceptibility to cytotoxic therapy. Immune-enriched meningiomas (38%) have intermediate outcomes and are distinguished by immune infiltration, HLA expression and lymphatic vessels. Hypermitotic meningiomas (28%) have the worst outcomes and are distinguished by convergent genetic and epigenetic mechanisms driving the cell cycle and resistance to cytotoxic therapy. To translate these findings into clinical practice, we show cytostatic cell cycle inhibitors attenuate meningioma growth in cell culture, organoids, xenografts and patients.

  View details for DOI 10.1038/s41588-022-01061-8

  View details for PubMedID 35534562

  View details for PubMedCentralID PMC9374001

• Combining radiomics and deep convolutional neural network features from preoperative MRI for predicting clinically relevant genetic biomarkers in glioblastoma. Neuro-oncology advances Calabrese, E., Rudie, J. D., Rauschecker, A. M., Villanueva-Meyer, J. E., Clarke, J. L., Solomon, D. A., Cha, S. 2022; 4 (1): vdac060

  Abstract

  Glioblastoma is the most common primary brain malignancy, yet treatment options are limited, and prognosis remains guarded. Individualized tumor genetic assessment has become important for accurate prognosis and for guiding emerging targeted therapies. However, challenges remain for widespread tumor genetic testing due to costs and the need for tissue sampling. The aim of this study is to evaluate a novel artificial intelligence method for predicting clinically relevant genetic biomarkers from preoperative brain MRI in patients with glioblastoma.We retrospectively analyzed preoperative MRI data from 400 patients with glioblastoma, IDH-wildtype or WHO grade 4 astrocytoma, IDH mutant who underwent resection and genetic testing. Nine genetic biomarkers were assessed: hotspot mutations of IDH1 or TERT promoter, pathogenic mutations of TP53, PTEN, ATRX, or CDKN2A/B, MGMT promoter methylation, EGFR amplification, and combined aneuploidy of chromosomes 7 and 10. Models were developed to predict biomarker status from MRI data using radiomics features, convolutional neural network (CNN) features, and a combination of both.Combined model performance was good for IDH1 and TERT promoter hotspot mutations, pathogenic mutations of ATRX and CDKN2A/B, and combined aneuploidy of chromosomes 7 and 10, with receiver operating characteristic area under the curve (ROC AUC) >0.85 and was fair for all other tested biomarkers with ROC AUC >0.7. Combined model performance was statistically superior to individual radiomics and CNN feature models for prediction chromosome 7 and 10 aneuploidy, MGMT promoter methylation, and PTEN mutation.Combining radiomics and CNN features from preoperative MRI yields improved noninvasive genetic biomarker prediction performance in patients with WHO grade 4 diffuse astrocytic gliomas.

  View details for DOI 10.1093/noajnl/vdac060

  View details for PubMedID 35611269

  View details for PubMedCentralID PMC9122791

• High-grade glioma with pleomorphic and pseudopapillary features (HPAP): a proposed type of circumscribed glioma in adults harboring frequent TP53 mutations and recurrent monosomy 13. Acta neuropathologica Pratt, D., Abdullaev, Z., Papanicolau-Sengos, A., Ketchum, C., Panneer Selvam, P., Chung, H. J., Lee, I., Raffeld, M., Gilbert, M. R., Armstrong, T. S., Pytel, P., Borys, E., Klonoski, J. M., McCord, M., Horbinski, C., Brat, D., Perry, A., Solomon, D., Eberhart, C., Giannini, C., Quezado, M., Aldape, K. 2022; 143 (3): 403-414

  Abstract

  Tumors of the central nervous system (CNS) often display a wide morphologic spectrum that has, until recently, been the sole basis for tumor classification. The introduction of the integrated histomolecular diagnostic approach in CNS tumors has facilitated a classification system that is increasingly data-driven and with improved alignment to clinical outcome. Here, we report a previously uncharacterized glioma type (n = 31) using unsupervised clustering analysis of DNA methylation array data from approximately 14,000 CNS tumor samples. Histologic examination revealed circumscribed growth and morphologic similarities to pleomorphic xanthoastrocytoma (PXA), astroblastoma, ependymoma, polymorphous neuroepithelial tumor of the young (PLNTY), and IDH-wildtype glioblastoma (GBM). Median age (46.5 years) was significantly older than other circumscribed gliomas and younger than GBM. Dimensionality reduction with uniform manifold approximation and projection (UMAP) and hierarchical clustering confirmed a methylation signature distinct from known tumor types and methylation classes. DNA sequencing revealed recurrent mutations in TP53 (57%), RB1 (26%), NF1 (26%), and NF2 (14%). BRAF V600E mutations were detected in 3/27 sequenced cases (12%). Copy number analysis showed increased whole chromosome aneuploidy with recurrent loss of chromosome 13 (28/31 cases, 90%). CDKN2A/B deletion (2/31, 6%) and MGMT promoter methylation (1/31, 3%) were notably rare events. Most tumors showed features of a high-grade glioma, yet survival data showed significantly better overall survival compared to GBM (p < 0.0001). In summary, we describe a previously uncharacterized glioma of adults identified by a distinct DNA methylation signature and recurrent loss of chromosome 13.

  View details for DOI 10.1007/s00401-022-02404-9

  View details for PubMedID 35103816

  View details for PubMedCentralID PMC9844519

• Activating NTRK2 and ALK receptor tyrosine kinase fusions extend the molecular spectrum of pleomorphic xanthoastrocytomas of early childhood: a diagnostic overlap with infant-type hemispheric glioma. Acta neuropathologica Lucas, C. G., Abdullaev, Z., Bruggers, C. S., Mirchia, K., Whipple, N. S., Alashari, M. M., Lowichik, A., Cheshier, S., Phillips, J. J., Devine, P., Solomon, D. A., Quezado, M., Aldape, K. D., Perry, A. 2022; 143 (2): 283-286

  View details for DOI 10.1007/s00401-021-02396-y

  View details for PubMedID 34910220

  View details for PubMedCentralID PMC8742815

• EWSR1-BEND2 fusion defines an epigenetically distinct subtype of astroblastoma. Acta neuropathologica Lucas, C. G., Gupta, R., Wu, J., Shah, K., Ravindranathan, A., Barreto, J., Gener, M., Ginn, K. F., Prall, O. W., Xu, H., Kee, D., Ko, H. S., Yaqoob, N., Zia, N., Florez, A., Cha, S., Perry, A., Clarke, J. L., Chang, S. M., Berger, M. S., Solomon, D. A. 2022; 143 (1): 109-113

  View details for DOI 10.1007/s00401-021-02388-y

  View details for PubMedID 34825267

  View details for PubMedCentralID PMC8732961

• Genetic and epigenetic characterization of posterior pituitary tumors. Acta neuropathologica Schmid, S., Solomon, D. A., Perez, E., Thieme, A., Kleinschmidt-DeMasters, B. K., Giannini, C., Reinhardt, A., Asa, S. L., Mete, O., Stichel, D., Siewert, C., Dittmayer, C., Hasselblatt, M., Paulus, W., Nagel, C., Harter, P. N., Schittenhelm, J., Honegger, J., Rushing, E., Coras, R., Pfister, S. M., Buslei, R., Koch, A., Perry, A., Jones, D. T., von Deimling, A., Capper, D., Lopes, M. B. 2021; 142 (6): 1025-1043

  Abstract

  Pituicytoma (PITUI), granular cell tumor (GCT), and spindle cell oncocytoma (SCO) are rare tumors of the posterior pituitary. Histologically, they may be challenging to distinguish and have been proposed to represent a histological spectrum of a single entity. We performed targeted next-generation sequencing, DNA methylation profiling, and copy number analysis on 47 tumors (14 PITUI; 12 GCT; 21 SCO) to investigate molecular features and explore possibilities of clinically meaningful tumor subclassification. We detected two main epigenomic subgroups by unsupervised clustering of DNA methylation data, though the overall methylation differences were subtle. The largest group (n = 23) contained most PITUIs and a subset of SCOs and was enriched for pathogenic mutations within genes in the MAPK/PI3K pathways (12/17 [71%] of sequenced tumors: FGFR1 (3), HRAS (3), BRAF (2), NF1 (2), CBL (1), MAP2K2 (1), PTEN (1)) and two with accompanying TERT promoter mutation. The second group (n = 16) contained most GCTs and a subset of SCOs, all of which mostly lacked identifiable genetic drivers. Outcome analysis demonstrated that the presence of chromosomal imbalances was significantly associated with reduced progression-free survival especially within the combined PITUI and SCO group (p = 0.031). In summary, we observed only subtle DNA methylation differences between posterior pituitary tumors, indicating that these tumors may be best classified as subtypes of a single entity. Nevertheless, our data indicate differences in mutation patterns and clinical outcome. For a clinically meaningful subclassification, we propose a combined histo-molecular approach into three subtypes: one subtype is defined by granular cell histology, scarcity of identifiable oncogenic mutations, and favorable outcome. The other two subtypes have either SCO or PITUI histology but are segregated by chromosomal copy number profile into a favorable group (no copy number changes) and a less favorable group (copy number imbalances present). Both of the latter groups have recurrent MAPK/PI3K genetic alterations that represent potential therapeutic targets.

  View details for DOI 10.1007/s00401-021-02377-1

  View details for PubMedID 34661724

  View details for PubMedCentralID PMC8568760

• A multicenter analysis of the prognostic value of histone H3 K27M mutation in adult high-grade spinal glioma. Journal of neurosurgery. Spine Akinduro, O. O., Garcia, D. P., Higgins, D. M., Vivas-Buitrago, T., Jentoft, M., Solomon, D. A., Daniels, D. J., Pennington, Z., Sherman, W. J., Delgardo, M., Bydon, M., Kalani, M. A., Zanazzi, G., Tsankova, N., Bendok, B. R., McCormick, P. C., Sciubba, D. M., Lo, S. L., Clarke, J. L., Abode-Iyamah, K., Quiñones-Hinojosa, A. 2021; 35 (6): 834-843

  Abstract

  High-grade spinal glioma (HGSG) is a rare but aggressive tumor that occurs in both adults and children. Histone H3 K27M mutation correlates with poor prognosis in children with diffuse midline glioma. However, the role of H3 K27M mutation in the prognosis of adults with HGSG remains unclear owing to the rarity of this mutation, conflicting reports, and the absence of multicenter studies on this topic.The authors studied a cohort of 30 adult patients with diffuse HGSG who underwent histological confirmation of diagnosis, surgical intervention, and treatment between January 2000 and July 2020 at six tertiary academic centers. The primary outcome was the effect of H3 K27M mutation status on progression-free survival (PFS) and overall survival (OS).Thirty patients (18 males and 12 females) with a median (range) age of 50.5 (19-76) years were included in the analysis. Eighteen patients had H3 K27M mutation-positive tumors, and 12 had H3 K27M mutation-negative tumors. The median (interquartile range) PFS was 3 (10) months, and the median (interquartile range) OS was 9 (23) months. The factors associated with increased survival were treatment with concurrent chemotherapy/radiation (p = 0.006 for PFS, and p ≤ 0.001 for OS) and American Spinal Injury Association grade C or better at presentation (p = 0.043 for PFS, and p < 0.001 for OS). There were no significant differences in outcomes based on tumor location, extent of resection, sex, or H3 K27M mutation status. Analysis restricted to HGSG containing necrosis and/or microvascular proliferation (WHO grade IV histological features) revealed increased OS for patients with H3 K27M mutation-positive tumors (p = 0.017).Although H3 K27M mutant-positive HGSG was associated with poor outcomes in adult patients, the outcomes of patients with H3 K27M mutant-positive HGSG were somewhat more favorable compared with those of their H3 K27M mutant-negative HGSG counterparts. Further preclinical animal studies and larger clinical studies are needed to further understand the age-dependent effects of H3 K27M mutation.

  View details for DOI 10.3171/2021.2.SPINE201675

  View details for PubMedID 34416733

• Deconvoluting Mechanisms of Acquired Resistance to RAF Inhibitors in BRAFV600E-Mutant Human Glioma. Clinical cancer research : an official journal of the American Association for Cancer Research Schreck, K. C., Morin, A., Zhao, G., Allen, A. N., Flannery, P., Glantz, M., Green, A. L., Jones, C., Jones, K. L., Kilburn, L. B., Nazemi, K. J., Samuel, D., Sanford, B., Solomon, D. A., Wang, J., Pratilas, C. A., Nicolaides, T., Mulcahy Levy, J. M. 2021; 27 (22): 6197-6208

  Abstract

  Selective RAF-targeted therapy is effective in some patients with BRAFV600E-mutated glioma, though emergent and adaptive resistance occurs through ill-defined mechanisms.Paired pre-/post- RAF inhibitor (RAFi)-treated glioma samples (N = 15) were obtained and queried for treatment-emergent genomic alterations using DNA and RNA sequencing (RNA-seq). Functional validation of putative resistance mechanisms was performed using established and patient-derived BRAFV600E-mutant glioma cell lines.Analysis of 15 tissue sample pairs identified 13 alterations conferring putative resistance were identified among nine paired samples (including mutations involving ERRFI1, BAP1, ANKHD1, and MAP2K1). We performed functional validation of mechanisms of resistance, including loss of NF1, PTEN, or CBL, in BRAFV600E-mutant glioma lines, and demonstrate they are capable of conferring resistance in vitro. Knockdown of CBL resulted in increased EGFR expression and phosphorylation, a possible mechanism for maintaining ERK signaling within the cell. Combination therapy with a MEKi or EGFR inhibitor was able to overcome resistance to BRAFi, in NF1 knockdown and CBL knockdown, respectively. Restoration of wild-type PTEN in B76 cells (PTEN-/-) restored sensitivity to BRAFi. We identified and validated CRAF upregulation as a mechanism of resistance in one resistant sample. RNA-seq analysis identified two emergent expression patterns in resistant samples, consistent with expression patterns of known glioma subtypes.Resistance mechanisms to BRAFi in glioma are varied and may predict effective precision combinations of targeted therapy, highlighting the importance of a personalized approach.

  View details for DOI 10.1158/1078-0432.CCR-21-2660

  View details for PubMedID 34433654

  View details for PubMedCentralID PMC8595717

• Diffuse hemispheric glioma, H3 G34-mutant: Genomic landscape of a new tumor entity and prospects for targeted therapy. Neuro-oncology Lucas, C. G., Mueller, S., Reddy, A., Taylor, J. W., Oberheim Bush, N. A., Clarke, J. L., Chang, S. M., Gupta, N., Berger, M. S., Perry, A., Phillips, J. J., Solomon, D. A. 2021; 23 (11): 1974-1976

  View details for DOI 10.1093/neuonc/noab184

  View details for PubMedID 34519829

  View details for PubMedCentralID PMC8628364

• Temozolomide-induced hypermutation is associated with distant recurrence and reduced survival after high-grade transformation of low-grade IDH-mutant gliomas. Neuro-oncology Yu, Y., Villanueva-Meyer, J., Grimmer, M. R., Hilz, S., Solomon, D. A., Choi, S., Wahl, M., Mazor, T., Hong, C., Shai, A., Phillips, J. J., Wainer, B. H., McDermott, M., Haas-Kogan, D., Taylor, J. W., Butowski, N., Clarke, J. L., Berger, M. S., Molinaro, A. M., Chang, S. M., Costello, J. F., Oberheim Bush, N. A. 2021; 23 (11): 1872-1884

  Abstract

  Chemotherapy improves overall survival after surgery and radiotherapy for newly diagnosed high-risk IDH-mutant low-grade gliomas (LGGs), but a proportion of patients treated with temozolomide (TMZ) will develop recurrent tumors with TMZ-induced hypermutation. We aimed to determine the prevalence of TMZ-induced hypermutation at recurrence and prognostic implications.We sequenced recurrent tumors from 82 patients with initially low-grade IDH-mutant gliomas who underwent reoperation and correlated hypermutation status with grade at recurrence and subsequent clinical outcomes.Hypermutation was associated with high-grade disease at the time of reoperation (OR 12.0 95% CI 2.5-115.5, P = .002) and was identified at transformation in 57% of recurrent LGGs previously exposed to TMZ. After anaplastic (grade III) transformation, hypermutation was associated with shorter survival on univariate and multivariate analysis (HR 3.4, 95% CI 1.2-9.9, P = .024), controlling for tumor grade, subtype, age, and prior radiotherapy. The effect of hypermutation on survival after transformation was validated in an independent, published dataset. Hypermutated (HM) tumors were more likely to develop discontiguous foci of disease in the brain and spine (P = .003). To estimate the overall incidence of high-grade transformation among low-grade IDH-mutant tumors, data from a phase II trial of TMZ for LGG were analyzed. Eight-year transformation-free survival was 53.8% (95% CI 42.8-69.2), and 61% of analyzed transformed cases were HM.TMZ-induced hypermutation is a common event in transformed LGG previously treated with TMZ and is associated with worse prognosis and development of discontiguous disease after recurrence. These findings impact tumor classification at recurrence, prognostication, and clinical trial design.

  View details for DOI 10.1093/neuonc/noab081

  View details for PubMedID 33823014

  View details for PubMedCentralID PMC8563321

• Tumor DNA requirements for accurate epigenetic-based classification of CNS neoplasia. Neuro-oncology Wu, J., Gupta, R., Barreto, J., Doo, P., Joseph, N. M., Lee, J. C., Perry, A., Chang, S. M., Berger, M. S., Solomon, D. A. 2021; 23 (10): 1798-1800

  View details for DOI 10.1093/neuonc/noab157

  View details for PubMedID 34351421

  View details for PubMedCentralID PMC8485446

• Adjuvant Maintenance Larotrectinib Therapy in 2 Children With NTRK Fusion-positive High-grade Cancers. Journal of pediatric hematology/oncology Carter-Febres, M., Schneller, N., Fair, D., Solomon, D., Perry, A., Roy, A., Linscott, L., Alashari, M., Kestle, J. R., Bruggers, C. S. 2021; 43 (7): e987-e990

  Abstract

  Treatment-related morbidity drives research to identify targetable lesions in children with cancer. Neurotrophic tropomyosin receptor kinase (NTRK) alterations occur in ~1% of pediatric solid tumors. Early phase pediatric trials involving the NTRK inhibitor treatment for progressive NTRK-mutated cancers show promising results. The authors describe the adjuvant maintenance larotrectinib treatment after definitive surgical resection in 2 toddlers with NTRK fusion-positive malignancies (ETV6-NTRK3 fusion-positive undifferentiated embryonal sarcoma of the kidney and NACC2-NTRK2 fusion-positive anaplastic astrocytoma). Both are alive, in remission, developing normally and tolerating larotrectinib 15 months later, thus extending the NTRK inhibitor therapeutic spectrum by describing the adjuvant maintenance larotrectinib treatment in children with NTRK fusion-positive cancers associated with high recurrences.

  View details for DOI 10.1097/MPH.0000000000001983

  View details for PubMedID 33093355

• Molecular characterisation of sporadic endolymphatic sac tumours and comparison to von Hippel-Lindau disease-related tumours. Neuropathology and applied neurobiology Schweizer, L., Thierfelder, F., Thomas, C., Soschinski, P., Kim, H. Y., Jödicke, R., Woltering, N., Förster, A., Teichmann, D., Siewert, C., Klein, K., Schmid, S., Nunninger, M., Thomale, U. W., Onken, J., Mühleisen, H., Schittenhelm, J., Tatagiba, M., von Deimling, A., Reuss, D. E., Solomon, D. A., Heppner, F. L., Koch, A., Hartmann, C., Staszewski, O., Capper, D. 2021; 47 (6): 756-767

  Abstract

  Although inactivation of the von Hippel-Lindau gene (VHL) on chromosome 3p25 is considered to be the major cause of hereditary endolymphatic sac tumours (ELSTs), the genetic background of sporadic ELST is largely unknown. The aim of this study was to determine the prevalence of VHL mutations in sporadic ELSTs and compare their characteristics to VHL-disease-related tumours.Genetic and epigenetic alterations were compared between 11 sporadic and 11 VHL-disease-related ELSTs by targeted sequencing and DNA methylation analysis.VHL mutations and small deletions detected by targeted deep sequencing were identified in 9/11 sporadic ELSTs (82%). No other cancer-related genetic pathway was altered except for TERT promoter mutations in two sporadic ELST and one VHL-disease-related ELST (15%). Loss of heterozygosity of chromosome 3 was found in 6/10 (60%) VHL-disease-related and 10/11 (91%) sporadic ELSTs resulting in biallelic VHL inactivation in 8/10 (73%) sporadic ELSTs. DNA methylation profiling did not reveal differences between sporadic and VHL-disease-related ELSTs but reliably distinguished ELST from morphological mimics of the cerebellopontine angle. VHL patients were significantly younger at disease onset compared to sporadic ELSTs (29 vs. 52 years, p < 0.0001, Fisher's exact test). VHL-disease status was not associated with an increased risk of recurrence, but the presence of clear cells was found to be associated with shorter progression-free survival (p = 0.0002, log-rank test).Biallelic inactivation of VHL is the main mechanism underlying ELSTs, but unknown mechanisms beyond VHL may rarely be involved in the pathogenesis of sporadic ELSTs.

  View details for DOI 10.1111/nan.12741

  View details for PubMedID 34091929

• Systemic and Craniospinal Rosai Dorfman Disease with Intraparenchymal, Intramedullary and Leptomeningeal Disease. International journal of hematology-oncology and stem cell research Li, Y., Sloan, E., Bollen, A., Solomon, D., Theodosopoulos, P., Cha, S. 2021; 15 (4): 260-264

  Abstract

  Rosai Dorfman disease is a rare histiocytic disorder of over-production of non-Langerhans histiocytes, which typically manifests with massive lymphadenopathy and sinonasal involvement. We report a rare case of systemic and disseminated craniospinal Rosai Dorfman disease with intraparenchymal and leptomeningeal involvement, but no sinus or dural-based disease. The diagnosis was established by biopsy of a hypothalamic mass. Additionally, UCSF500 Next Generation Sequencing demonstrated a solitary pathogenic alteration affecting the BRAF oncogene, which supports the morphologic and immunohistochemical diagnosis of Rosai-Dorfman disease.

  View details for DOI 10.18502/ijhoscr.v15i4.7482

  View details for PubMedID 35291666

  View details for PubMedCentralID PMC8888355

• Sarcomatous Meningioma: Diagnostic Pitfalls and the Utility of Molecular Testing. Journal of neuropathology and experimental neurology Lucas, C. G., Devine, P., Solomon, D. A., Giannini, C., Reifenberger, G., Dahiya, S., Caccamo, D., Perry, A. 2021; 80 (8): 764-768

  Abstract

  Anaplastic meningiomas can have a sarcomatous appearance on histology but true sarcomatous (metaplastic) differentiation is rare. These tumors follow an aggressive clinical course with recurrence and poor clinical outcomes. Due to significant overlap in morphology and immunohistochemical profiles, distinguishing between sarcomatous transformation of a meningioma and a true sarcoma can be challenging. Here, we outline potential diagnostic pitfalls and the utility of ancillary molecular testing in 3 patients diagnosed with sarcomatous meningiomas. We report loss of typical meningothelial markers in sarcomatous meningiomas. Ancillary molecular testing can support the diagnosis of sarcomatous meningioma when a molecular signature consistent with meningioma is seen, such as inactivation of the NF2 gene. Recognition of this rare transformation in meningioma can prevent a misdiagnosis of a primary sarcoma, whether sporadic or radiation-induced from prior treatment of a more classic meningioma.

  View details for DOI 10.1093/jnen/nlab053

  View details for PubMedID 34128073

  View details for PubMedCentralID PMC9432138

• Low-grade glioneuronal tumors with FGFR2 fusion resolve into a single epigenetic group corresponding to 'Polymorphous low-grade neuroepithelial tumor of the young'. Acta neuropathologica Gupta, R., Lucas, C. G., Wu, J., Barreto, J., Shah, K., Simon, I. B., Casavilca-Zambrano, S., Brathwaite, C., Zhou, H., Caccamo, D., Gilani, A., Kleinschmidt-DeMasters, B. K., Lee, J. C., Perry, A., Clarke, J. L., Chang, S. M., Berger, M. S., Solomon, D. A. 2021; 142 (3): 595-599

  View details for DOI 10.1007/s00401-021-02352-w

  View details for PubMedID 34322742

  View details for PubMedCentralID PMC8357689

• Intracranial mesenchymal tumor with FET-CREB fusion-A unifying diagnosis for the spectrum of intracranial myxoid mesenchymal tumors and angiomatoid fibrous histiocytoma-like neoplasms. Brain pathology (Zurich, Switzerland) Sloan, E. A., Chiang, J., Villanueva-Meyer, J. E., Alexandrescu, S., Eschbacher, J. M., Wang, W., Mafra, M., Ud Din, N., Carr-Boyd, E., Watson, M., Punsoni, M., Oviedo, A., Gilani, A., Kleinschmidt-DeMasters, B. K., Coss, D. J., Lopes, M. B., Raffel, C., Berger, M. S., Chang, S. M., Reddy, A., Ramani, B., Ferris, S. P., Lee, J. C., Hofmann, J. W., Cho, S. J., Horvai, A. E., Pekmezci, M., Tihan, T., Bollen, A. W., Rodriguez, F. J., Ellison, D. W., Perry, A., Solomon, D. A. 2021; 31 (4): e12918

  Abstract

  Intracranial mesenchymal tumors with FET-CREB fusions are a recently described group of neoplasms in children and young adults characterized by fusion of a FET family gene (usually EWSR1, but rarely FUS) to a CREB family transcription factor (ATF1, CREB1, or CREM), and have been variously termed intracranial angiomatoid fibrous histiocytoma or intracranial myxoid mesenchymal tumor. The clinical outcomes, histologic features, and genomic landscape are not well defined. Here, we studied 20 patients with intracranial mesenchymal tumors proven to harbor FET-CREB fusion by next-generation sequencing (NGS). The 16 female and four male patients had a median age of 14 years (range 4-70). Tumors were uniformly extra-axial or intraventricular and located at the cerebral convexities (n = 7), falx (2), lateral ventricles (4), tentorium (2), cerebellopontine angle (4), and spinal cord (1). NGS demonstrated that eight tumors harbored EWSR1-ATF1 fusion, seven had EWSR1-CREB1, four had EWSR1-CREM, and one had FUS-CREM. Tumors were uniformly well circumscribed and typically contrast enhancing with solid and cystic growth. Tumors with EWSR1-CREB1 fusions more often featured stellate/spindle cell morphology, mucin-rich stroma, and hemangioma-like vasculature compared to tumors with EWSR1-ATF1 fusions that most often featured sheets of epithelioid cells with mucin-poor collagenous stroma. These tumors demonstrated polyphenotypic immunoprofiles with frequent positivity for desmin, EMA, CD99, MUC4, and synaptophysin, but absence of SSTR2A, myogenin, and HMB45 expression. There was a propensity for local recurrence with a median progression-free survival of 12 months and a median overall survival of greater than 60 months, with three patients succumbing to disease (all with EWSR1-ATF1 fusions). In combination with prior case series, this study provides further insight into intracranial mesenchymal tumors with FET-CREB fusion, which represent a distinct group of CNS tumors encompassing both intracranial myxoid mesenchymal tumor and angiomatoid fibrous histiocytoma-like neoplasms.

  View details for DOI 10.1111/bpa.12918

  View details for PubMedID 33141488

  View details for PubMedCentralID PMC8089120

• Letter: Patterns of Intermediate- and High-Risk Meningioma Recurrence After Treatment With Postoperative External Beam Radiotherapy. Neurosurgery Susko, M. S., Chen, W. C., Vasudevan, H. N., Magill, S. T., Lucas, C. G., Oberheim Bush, N. A., Solomon, D. A., Theodosopoulos, P. V., McDermott, M. W., Villanueva-Meyer, J. E., Boreta, L., Nakamura, J. L., Sneed, P. K., Braunstein, S. E., Raleigh, D. R. 2021; 89 (1): E99-E101

  View details for DOI 10.1093/neuros/nyab143

  View details for PubMedID 33887769

  View details for PubMedCentralID PMC8203419

• A subset of pediatric-type thalamic gliomas share a distinct DNA methylation profile, H3K27me3 loss and frequent alteration of EGFR. Neuro-oncology Sievers, P., Sill, M., Schrimpf, D., Stichel, D., Reuss, D. E., Sturm, D., Hench, J., Frank, S., Krskova, L., Vicha, A., Zapotocky, M., Bison, B., Castel, D., Grill, J., Debily, M. A., Harter, P. N., Snuderl, M., Kramm, C. M., Reifenberger, G., Korshunov, A., Jabado, N., Wesseling, P., Wick, W., Solomon, D. A., Perry, A., Jacques, T. S., Jones, C., Witt, O., Pfister, S. M., von Deimling, A., Jones, D. T., Sahm, F. 2021; 23 (1): 34-43

  Abstract

  Malignant astrocytic gliomas in children show a remarkable biological and clinical diversity. Small in-frame insertions or missense mutations in the epidermal growth factor receptor gene (EGFR) have recently been identified in a distinct subset of pediatric-type bithalamic gliomas with a unique DNA methylation pattern.Here, we investigated an epigenetically homogeneous cohort of malignant gliomas (n = 58) distinct from other subtypes and enriched for pediatric cases and thalamic location, in comparison with this recently identified subtype of pediatric bithalamic gliomas.EGFR gene amplification was detected in 16/58 (27%) tumors, and missense mutations or small in-frame insertions in EGFR were found in 20/30 tumors with available sequencing data (67%; 5 of them co-occurring with EGFR amplification). Additionally, 8 of the 30 tumors (27%) harbored an H3.1 or H3.3 K27M mutation (6 of them with a concomitant EGFR alteration). All tumors tested showed loss of H3K27me3 staining, with evidence of overexpression of the EZH inhibitory protein (EZHIP) in the H3 wildtype cases. Although some tumors indeed showed a bithalamic growth pattern, a significant proportion of tumors occurred in the unilateral thalamus or in other (predominantly midline) locations.Our findings present a distinct molecular class of pediatric-type malignant gliomas largely overlapping with the recently reported bithalamic gliomas characterized by EGFR alteration, but additionally showing a broader spectrum of EGFR alterations and tumor localization. Global H3K27me3 loss in this group appears to be mediated by either H3 K27 mutation or EZHIP overexpression. EGFR inhibition may represent a potential therapeutic strategy in these highly aggressive gliomas.

  View details for DOI 10.1093/neuonc/noaa251

  View details for PubMedID 33130881

  View details for PubMedCentralID PMC7850075

• A Prognostic Gene-Expression Signature and Risk Score for Meningioma Recurrence After Resection. Neurosurgery Chen, W. C., Vasudevan, H. N., Choudhury, A., Pekmezci, M., Lucas, C. G., Phillips, J., Magill, S. T., Susko, M. S., Braunstein, S. E., Oberheim Bush, N. A., Boreta, L., Nakamura, J. L., Villanueva-Meyer, J. E., Sneed, P. K., Perry, A., McDermott, M. W., Solomon, D. A., Theodosopoulos, P. V., Raleigh, D. R. 2020; 88 (1): 202-210

  Abstract

  Prognostic markers for meningioma are needed to risk-stratify patients and guide postoperative surveillance and adjuvant therapy.To identify a prognostic gene signature for meningioma recurrence and mortality after resection using targeted gene-expression analysis.Targeted gene-expression analysis was used to interrogate a discovery cohort of 96 meningiomas and an independent validation cohort of 56 meningiomas with comprehensive clinical follow-up data from separate institutions. Bioinformatic analysis was used to identify prognostic genes and generate a gene-signature risk score between 0 and 1 for local recurrence.We identified a 36-gene signature of meningioma recurrence after resection that achieved an area under the curve of 0.86 in identifying tumors at risk for adverse clinical outcomes. The gene-signature risk score compared favorably to World Health Organization (WHO) grade in stratifying cases by local freedom from recurrence (LFFR, P < .001 vs .09, log-rank test), shorter time to failure (TTF, F-test, P < .0001), and overall survival (OS, P < .0001 vs .07) and was independently associated with worse LFFR (relative risk [RR] 1.56, 95% CI 1.30-1.90) and OS (RR 1.32, 95% CI 1.07-1.64), after adjusting for clinical covariates. When tested on an independent validation cohort, the gene-signature risk score remained associated with shorter TTF (F-test, P = .002), compared favorably to WHO grade in stratifying cases by OS (P = .003 vs P = .10), and was significantly associated with worse OS (RR 1.86, 95% CI 1.19-2.88) on multivariate analysis.The prognostic meningioma gene-expression signature and risk score presented may be useful for identifying patients at risk for recurrence.

  View details for DOI 10.1093/neuros/nyaa355

  View details for PubMedID 32860417

  View details for PubMedCentralID PMC7735867

• The immunohistochemical, DNA methylation, and chromosomal copy number profile of cauda equina paraganglioma is distinct from extra-spinal paraganglioma. Acta neuropathologica Ramani, B., Gupta, R., Wu, J., Barreto, J., Bollen, A. W., Tihan, T., Mummaneni, P. V., Ames, C., Clark, A., Oberheim Bush, N. A., Butowski, N., Phillips, D., King, B. E., Bator, S. M., Treynor, E. C., Zherebitskiy, V., Quinn, P. S., Walker, J. B., Pekmezci, M., Sullivan, D. V., Hofmann, J. W., Sloan, E. A., M Chang, S., Berger, M. S., Solomon, D. A., Perry, A. 2020; 140 (6): 907-917

  Abstract

  Paragangliomas are neuroendocrine tumors of the autonomic nervous system that are variably clinically functional and have a potential for metastasis. Up to 40% occur in the setting of a hereditary syndrome, most commonly due to germline mutations in succinate dehydrogenase (SDHx) genes. Immunohistochemically, paragangliomas are characteristically GATA3-positive and cytokeratin-negative, with loss of SDHB expression in most hereditary cases. In contrast, the rare paragangliomas arising in the cauda equina (CEP) or filum terminale region have been shown to be hormonally silent, clinically indolent, and have variable keratin expression, suggesting these tumors may represent a separate pathologic entity. We retrospectively evaluated 17 CEPs from 11 male and 6 female patients with a median age of 38 years (range 21-82), none with a family history of neuroendocrine neoplasia. Six of the 17 tumors demonstrated prominent gangliocytic or ganglioneuromatous differentiation. By immunohistochemistry, none of the CEPs showed GATA3 positivity or loss of SDHB staining; all 17 CEPs were cytokeratin positive. Genome-wide DNA methylation profiling was performed on 12 of the tumors and compared with publicly available genome-wide DNA methylation data. Clustering analysis showed that CEPs form a distinct epigenetic group, separate from paragangliomas of extraspinal sites, pheochromocytomas, and other neuroendocrine neoplasms. Copy number analysis revealed diploid genomes in the vast majority of CEPs, whereas extraspinal paragangliomas were mostly aneuploid with recurrent trisomy 1q and monosomies of 1p, 3, and 11, none of which were present in the cohort of CEP. Together, these findings indicate that CEPs likely represent a distinct entity. Future genomic studies are needed to further elucidate the molecular pathogenesis of these tumors.

  View details for DOI 10.1007/s00401-020-02221-y

  View details for PubMedID 32892244

  View details for PubMedCentralID PMC7682537

• Clinical, radiologic, and genetic characteristics of histone H3 K27M-mutant diffuse midline gliomas in adults. Neuro-oncology advances Schulte, J. D., Buerki, R. A., Lapointe, S., Molinaro, A. M., Zhang, Y., Villanueva-Meyer, J. E., Perry, A., Phillips, J. J., Tihan, T., Bollen, A. W., Pekmezci, M., Butowski, N., Oberheim Bush, N. A., Taylor, J. W., Chang, S. M., Theodosopoulos, P., Aghi, M. K., Hervey-Jumper, S. L., Berger, M. S., Solomon, D. A., Clarke, J. L. 2020; 2 (1): vdaa142

  Abstract

  "Diffuse midline glioma (DMG), H3 K27M-mutant" is a new tumor entity established in the 2016 WHO classification of Tumors of the Central Nervous System that comprises a set of diffuse gliomas arising in midline structures and is molecularly defined by a K27M mutation in genes encoding the histone 3 variants H3.3 or H3.1. While this tumor entity is associated with poor prognosis in children, clinical experience in adults remains limited.Patient demographics, radiologic and pathologic characteristics, treatment course, progression, and patient survival were collected for 60 adult patients with DMG, H3 K27M-mutant. A subset of tumors also underwent next-generation sequencing. Analysis of progression-free survival and overall survival was conducted using Kaplan-Meier modeling, and univariate and multivariate analysis.Median patient age was 32 years (range 18-71 years). Tumors were centered in the thalamus (n = 34), spinal cord (10), brainstem (5), cerebellum (4), or other midline sites (4), or were multifocal (3). Genomic profiling revealed p.K27M mutations exclusively in the H3F3A gene and an absence of mutations in HIST1H3B or HIST1H3C, which are present in approximately one-third of pediatric DMGs. Accompanying mutations in TP53, PPM1D, FGFR1, NF1, and ATRX were frequently found. The overall survival of this adult cohort was 27.6 months, longer than historical averages for both H3 K27M-mutant DMG in children and IDH-wildtype glioblastoma in adults.Together, these findings indicate that H3 K27M-mutant DMG represents a heterogeneous disease with regard to outcomes, sites of origin, and molecular pathogenesis in adults versus children.

  View details for DOI 10.1093/noajnl/vdaa142

  View details for PubMedID 33354667

  View details for PubMedCentralID PMC7739048

• Comprehensive analysis of diverse low-grade neuroepithelial tumors with FGFR1 alterations reveals a distinct molecular signature of rosette-forming glioneuronal tumor. Acta neuropathologica communications Lucas, C. G., Gupta, R., Doo, P., Lee, J. C., Cadwell, C. R., Ramani, B., Hofmann, J. W., Sloan, E. A., Kleinschmidt-DeMasters, B. K., Lee, H. S., Wood, M. D., Grafe, M., Born, D., Vogel, H., Salamat, S., Puccetti, D., Scharnhorst, D., Samuel, D., Cooney, T., Cham, E., Jin, L., Khatib, Z., Maher, O., Chamyan, G., Brathwaite, C., Bannykh, S., Mueller, S., Kline, C. N., Banerjee, A., Reddy, A., Taylor, J. W., Clarke, J. L., Oberheim Bush, N. A., Butowski, N., Gupta, N., Auguste, K. I., Sun, P. P., Roland, J. L., Raffel, C., Aghi, M. K., Theodosopoulos, P., Chang, E., Hervey-Jumper, S., Phillips, J. J., Pekmezci, M., Bollen, A. W., Tihan, T., Chang, S., Berger, M. S., Perry, A., Solomon, D. A. 2020; 8 (1): 151

  Abstract

  The FGFR1 gene encoding fibroblast growth factor receptor 1 has emerged as a frequently altered oncogene in the pathogenesis of multiple low-grade neuroepithelial tumor (LGNET) subtypes including pilocytic astrocytoma, dysembryoplastic neuroepithelial tumor (DNT), rosette-forming glioneuronal tumor (RGNT), and extraventricular neurocytoma (EVN). These activating FGFR1 alterations in LGNET can include tandem duplication of the exons encoding the intracellular tyrosine kinase domain, in-frame gene fusions most often with TACC1 as the partner, or hotspot missense mutations within the tyrosine kinase domain (either at p.N546 or p.K656). However, the specificity of these different FGFR1 events for the various LGNET subtypes and accompanying genetic alterations are not well defined. Here we performed comprehensive genomic and epigenomic characterization on a diverse cohort of 30 LGNET with FGFR1 alterations. We identified that RGNT harbors a distinct epigenetic signature compared to other LGNET with FGFR1 alterations, and is uniquely characterized by FGFR1 kinase domain hotspot missense mutations in combination with either PIK3CA or PIK3R1 mutation, often with accompanying NF1 or PTPN11 mutation. In contrast, EVN harbors its own distinct epigenetic signature and is characterized by FGFR1-TACC1 fusion as the solitary pathogenic alteration. Additionally, DNT and pilocytic astrocytoma are characterized by either kinase domain tandem duplication or hotspot missense mutations, occasionally with accompanying NF1 or PTPN11 mutation, but lacking the accompanying PIK3CA or PIK3R1 mutation that characterizes RGNT. The glial component of LGNET with FGFR1 alterations typically has a predominantly oligodendroglial morphology, and many of the pilocytic astrocytomas with FGFR1 alterations lack the biphasic pattern, piloid processes, and Rosenthal fibers that characterize pilocytic astrocytomas with BRAF mutation or fusion. Together, this analysis improves the classification and histopathologic stratification of LGNET with FGFR1 alterations.

  View details for DOI 10.1186/s40478-020-01027-z

  View details for PubMedID 32859279

• A novel PARD3B-NUTM1 fusion in an aggressive primary CNS embryonal tumor in a young adult. Acta neuropathologica communications Ko, K., Kitani, T., Harris, B. T., Anaizi, A. N., Solomon, D., Perry, A., Toretsky, J., Ozdemirli, M. 2020; 8 (1): 112

  View details for DOI 10.1186/s40478-020-00991-w

  View details for PubMedID 32680570

  View details for PubMedCentralID PMC7368778

• cIMPACT-NOW update 6: new entity and diagnostic principle recommendations of the cIMPACT-Utrecht meeting on future CNS tumor classification and grading. Brain pathology (Zurich, Switzerland) Louis, D. N., Wesseling, P., Aldape, K., Brat, D. J., Capper, D., Cree, I. A., Eberhart, C., Figarella-Branger, D., Fouladi, M., Fuller, G. N., Giannini, C., Haberler, C., Hawkins, C., Komori, T., Kros, J. M., Ng, H. K., Orr, B. A., Park, S. H., Paulus, W., Perry, A., Pietsch, T., Reifenberger, G., Rosenblum, M., Rous, B., Sahm, F., Sarkar, C., Solomon, D. A., Tabori, U., van den Bent, M. J., von Deimling, A., Weller, M., White, V. A., Ellison, D. W. 2020; 30 (4): 844-856

  Abstract

  cIMPACT-NOW (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy) was established to evaluate and make practical recommendations on recent advances in the field of CNS tumor classification, particularly in light of the rapid progress in molecular insights into these neoplasms. For Round 2 of its deliberations, cIMPACT-NOW Working Committee 3 was reconstituted and convened in Utrecht, The Netherlands, for a meeting designed to review putative new CNS tumor types in advance of any future World Health Organization meeting on CNS tumor classification. In preparatory activities for the meeting and at the actual meeting, a list of possible entities was assembled and each type and subtype debated. Working Committee 3 recommended that a substantial number of newly recognized types and subtypes should be considered for inclusion in future CNS tumor classifications. In addition, the group endorsed a number of principles-relating to classification categories, approaches to classification, nomenclature, and grading-that the group hopes will also inform the future classification of CNS neoplasms.

  View details for DOI 10.1111/bpa.12832

  View details for PubMedID 32307792

  View details for PubMedCentralID PMC8018152

• Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes. Cancer discovery Clarke, M., Mackay, A., Ismer, B., Pickles, J. C., Tatevossian, R. G., Newman, S., Bale, T. A., Stoler, I., Izquierdo, E., Temelso, S., Carvalho, D. M., Molinari, V., Burford, A., Howell, L., Virasami, A., Fairchild, A. R., Avery, A., Chalker, J., Kristiansen, M., Haupfear, K., Dalton, J. D., Orisme, W., Wen, J., Hubank, M., Kurian, K. M., Rowe, C., Maybury, M., Crosier, S., Knipstein, J., Schüller, U., Kordes, U., Kram, D. E., Snuderl, M., Bridges, L., Martin, A. J., Doey, L. J., Al-Sarraj, S., Chandler, C., Zebian, B., Cairns, C., Natrajan, R., Boult, J. K., Robinson, S. P., Sill, M., Dunkel, I. J., Gilheeney, S. W., Rosenblum, M. K., Hughes, D., Proszek, P. Z., Macdonald, T. J., Preusser, M., Haberler, C., Slavc, I., Packer, R., Ng, H. K., Caspi, S., Popović, M., Faganel Kotnik, B., Wood, M. D., Baird, L., Davare, M. A., Solomon, D. A., Olsen, T. K., Brandal, P., Farrell, M., Cryan, J. B., Capra, M., Karremann, M., Schittenhelm, J., Schuhmann, M. U., Ebinger, M., Dinjens, W. N., Kerl, K., Hettmer, S., Pietsch, T., Andreiuolo, F., Driever, P. H., Korshunov, A., Hiddingh, L., Worst, B. C., Sturm, D., Zuckermann, M., Witt, O., Bloom, T., Mitchell, C., Miele, E., Colafati, G. S., Diomedi-Camassei, F., Bailey, S., Moore, A. S., Hassall, T. E., Lowis, S. P., Tsoli, M., Cowley, M. J., Ziegler, D. S., Karajannis, M. A., Aquilina, K., Hargrave, D. R., Carceller, F., Marshall, L. V., von Deimling, A., Kramm, C. M., Pfister, S. M., Sahm, F., Baker, S. J., Mastronuzzi, A., Carai, A., Vinci, M., Capper, D., Popov, S., Ellison, D. W., Jacques, T. S., Jones, D. T., Jones, C. 2020; 10 (7): 942-963

  Abstract

  Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an "intrinsic" spectrum of disease specific to the infant population. These included those with targetable MAPK alterations, and a large proportion of remaining cases harboring gene fusions targeting ALK (n = 31), NTRK1/2/3 (n = 21), ROS1 (n = 9), and MET (n = 4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a change in diagnostic practice and management. SIGNIFICANCE: Infant high-grade gliomas in the cerebral hemispheres comprise novel subgroups, with a prevalence of ALK, NTRK1/2/3, ROS1, or MET gene fusions. Kinase fusion-positive tumors have better outcome and respond to targeted therapy clinically. Other subgroups have poor outcome, with fusion-negative cases possibly representing an epigenetically driven pluripotent stem cell phenotype.See related commentary by Szulzewsky and Cimino, p. 904.This article is highlighted in the In This Issue feature, p. 890.

  View details for DOI 10.1158/2159-8290.CD-19-1030

  View details for PubMedID 32238360

  View details for PubMedCentralID PMC8313225

• Pathology of meningiomas. Handbook of clinical neurology Solomon, D. A., Pekmezci, M. 2020; 169: 87-99

  Abstract

  Meningiomas are a diverse group of neoplasms that exhibit a wide range of morphologies and clinical behavior. They are generally accepted to originate from arachnoid cap cells within the leptomeninges. Classic histologic features include whorl formations, psammoma bodies, nuclear holes, and nuclear pseudoinclusions. Meningiomas are classified as benign, atypical, or anaplastic (grades I, II, or III) based on histologic features including mitotic activity, brain invasion, and presence of other minor criteria. There are numerous histologic variants of meningiomas, and some are associated with worse clinical outcomes and therefore are assigned a higher grade. The majority of meningiomas show diffuse positivity for vimentin and epithelial membrane antigen, supporting the dual mesenchymal and epithelial nature of meningothelial cells. The presence of an elevated proliferation index (as measured by Ki-67 immunohistochemical stain) and loss of progesterone receptor expression are associated with the higher grade. Pathologic features including histologic variants, grading criteria, and ancillary tests such as special and immunohistochemical stains are discussed.

  View details for DOI 10.1016/B978-0-12-804280-9.00005-6

  View details for PubMedID 32553300

• DNA methylation profiling demonstrates superior diagnostic classification to RNA-sequencing in a case of metastatic meningioma. Acta neuropathologica communications Vasudevan, H. N., Castro, M. R., Lee, J. C., Villanueva-Meyer, J. E., Bush, N. A., McDermott, M. W., Solomon, D. A., Perry, A., Magill, S. T., Raleigh, D. R. 2020; 8 (1): 82

  Abstract

  Meningiomas are the most common primary intracranial tumors, but meningioma metastases are rare. Accordingly, the clinical workup, diagnostic testing, and molecular classification of metastatic meningioma is incompletely understood. Here, we present a case report of multiply recurrent meningioma complicated by liver metastasis. We discuss the patient presentation, imaging findings, and conventional histopathologic characterization of both the intracranial lesion and the metastatic focus. Further, we perform multiplatform molecular profiling, comprised of DNA methylation arrays and RNA-sequencing, of six stereotactically-guided samples from the intracranial meningioma and a single ultrasound-guided liver metastasis biopsy. Our results show that DNA methylation clusters distinguish the liver metastasis from the intracranial meningioma samples, and identify a small focus of hepatocyte contamination with the liver biopsy. Nonetheless, DNA methylation-based classification accurately identifies the liver metastasis as a meningioma with high confidence. We also find that clustering of RNA-sequencing results distinguishes the liver metastasis from the intracranial meningiomas samples, but that differential gene expression classification is confounded by hepatocyte-specific gene expression programs in the liver metastasis. In sum, this case report sheds light on the comparative biology of intracranial and metastatic meningioma. Furthermore, our results support methylation-based classification as a robust method of diagnosing metastatic lesions, underscore the broad utility of DNA methylation array profiling in diagnostic pathology, and caution against the routine use of bulk RNA-sequencing for identifying tumor signatures in heterogeneous metastatic lesions.

  View details for DOI 10.1186/s40478-020-00952-3

  View details for PubMedID 32517746

  View details for PubMedCentralID PMC7285578

• Next-Generation Sequencing of Retinoblastoma Identifies Pathogenic Alterations beyond RB1 Inactivation That Correlate with Aggressive Histopathologic Features. Ophthalmology Afshar, A. R., Pekmezci, M., Bloomer, M. M., Cadenas, N. J., Stevers, M., Banerjee, A., Roy, R., Olshen, A. B., Van Ziffle, J., Onodera, C., Devine, W. P., Grenert, J. P., Bastian, B. C., Solomon, D. A., Damato, B. E. 2020; 127 (6): 804-813

  Abstract

  To determine the usefulness of a comprehensive, targeted-capture next-generation sequencing (NGS) assay for the clinical management of children undergoing enucleation for retinoblastoma.Cohort study.Thirty-two children with retinoblastoma.We performed targeted NGS using the UCSF500 Cancer Panel (University of California, San Francisco, San Francisco, CA) on formalin-fixed, paraffin-embedded tumor tissue along with constitutional DNA isolated from peripheral blood, buccal swab, or uninvolved optic nerve. Peripheral blood samples were also sent to a commercial laboratory for germline RB1 mutation testing.Presence or absence of germline RB1 mutation or deletion, tumor genetic profile, and association of genetic alterations with clinicopathologic features.Germline mutation or deletion of the RB1 gene was identified in all children with bilateral retinoblastoma (n = 12), and these NGS results were 100% concordant with commercial germline RB1 mutation analysis. In tumor tissue tested with NGS, biallelic inactivation of RB1 was identified in 28 tumors and focal MYCN amplification was identified in 4 tumors (2 with wild-type RB1 and 2 with biallelic RB1 inactivation). Additional likely pathogenic alterations beyond RB1 were identified in 13 tumors (41%), several of which have not been reported previously in retinoblastoma. These included focal amplifications of MDM4 and RAF1, as well as damaging mutations involving BCOR, ARID1A, MGA, FAT1, and ATRX. The presence of additional likely pathogenetic mutations beyond RB1 inactivation was associated with aggressive histopathologic features, including higher histologic grade and anaplasia, and also with both unilateral and sporadic disease.Comprehensive NGS analysis reliably detects relevant mutations, amplifications, and chromosomal copy number changes in retinoblastoma. The presence of genetic alterations beyond RB1 inactivation correlates with aggressive histopathologic features.

  View details for DOI 10.1016/j.ophtha.2019.12.005

  View details for PubMedID 32139107

  View details for PubMedCentralID PMC7246167

• Multiregion exome sequencing of ovarian immature teratomas reveals 2N near-diploid genomes, paucity of somatic mutations, and extensive allelic imbalances shared across mature, immature, and disseminated components. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc Heskett, M. B., Sanborn, J. Z., Boniface, C., Goode, B., Chapman, J., Garg, K., Rabban, J. T., Zaloudek, C., Benz, S. C., Spellman, P. T., Solomon, D. A., Cho, R. J. 2020; 33 (6): 1193-1206

  Abstract

  Immature teratoma is a subtype of malignant germ cell tumor of the ovary that occurs most commonly in the first three decades of life, frequently with bilateral ovarian disease. Despite being the second most common malignant germ cell tumor of the ovary, little is known about its genetic underpinnings. Here we performed multiregion whole-exome sequencing to interrogate the genetic zygosity, clonal relationship, DNA copy number, and mutational status of 52 pathologically distinct tumor components from ten females with ovarian immature teratomas, with bilateral tumors present in five cases and peritoneal dissemination in seven cases. We found that ovarian immature teratomas are genetically characterized by 2N near-diploid genomes with extensive loss of heterozygosity and an absence of genes harboring recurrent somatic mutations or known oncogenic variants. All components within a single ovarian tumor (immature teratoma, mature teratoma with different histologic patterns of differentiation, and yolk sac tumor) were found to harbor an identical pattern of loss of heterozygosity across the genome, indicating a shared clonal origin. In contrast, the four analyzed bilateral teratomas showed distinct patterns of zygosity changes in the right versus left sided tumors, indicating independent clonal origins. All disseminated teratoma components within the peritoneum (including gliomatosis peritonei) shared a clonal pattern of loss of heterozygosity with either the right or left primary ovarian tumor. The observed genomic loss of heterozygosity patterns indicate that diverse meiotic errors contribute to the formation of ovarian immature teratomas, with 11 out of the 15 genetically distinct clones determined to result from nondisjunction errors during meiosis I or II. Overall, these findings suggest that copy-neutral loss of heterozygosity resulting from meiotic abnormalities may be sufficient to generate ovarian immature teratomas from germ cells.

  View details for DOI 10.1038/s41379-019-0446-y

  View details for PubMedID 31911616

  View details for PubMedCentralID PMC7286805

• Eye-sparing Treatment of Localized Orbital Medulloepithelioma With Neoadjuvant Chemoradiation. Ophthalmic plastic and reconstructive surgery Gallo, R. A., Shoag, J., Johnson, T. E., Solomon, D. A., Perry, A., Podda, A., Lee, J. Y., Rong, A. J. 2020; 37 (1): e13-e16

  Abstract

  A 9-year-old girl presented with a 3-day history of progressive proptosis accompanied by transient discomfort and blurry vision in the OD. MRI revealed a heterogeneously enhancing intraconal lesion that partially encased and displaced the optic nerve. There was no intraocular or intracranial involvement, nor were there signs of distant metastasis. Histopathologic evaluation and immunohistochemistry were consistent with orbital medulloepithelioma. The patient received 4 cycles of chemoradiation per a retinoblastoma protocol. Repeat MRI scans showed significant tumor regression, and further surgical debulking was performed. There has been no evidence of recurrence for over 14 months. Herein, the authors describe an eye-sparing, multimodal treatment of a rare case of localized orbital medulloepithelioma.

  View details for DOI 10.1097/IOP.0000000000001703

  View details for PubMedID 32427730

• Gliomas arising in the setting of Li-Fraumeni syndrome stratify into two molecular subgroups with divergent clinicopathologic features. Acta neuropathologica Sloan, E. A., Hilz, S., Gupta, R., Cadwell, C., Ramani, B., Hofmann, J., Kline, C. N., Banerjee, A., Reddy, A., Oberheim Bush, N. A., Chang, S., Braunstein, S., Chang, E. F., Raffel, C., Gupta, N., Sun, P. P., Kim, J. Y., Moes, G., Alva, E., Li, R., Bruggers, C. S., Alashari, M., Wetmore, C., Garg, S., Dishop, M., Van Ziffle, J., Onodera, C., Devine, P., Grenert, J. P., Lee, J. C., Phillips, J. J., Pekmezci, M., Tihan, T., Bollen, A. W., Berger, M. S., Costello, J. F., Perry, A., Solomon, D. A. 2020; 139 (5): 953-957

  View details for DOI 10.1007/s00401-020-02144-8

  View details for PubMedID 32157385

  View details for PubMedCentralID PMC7183424

• Myxoid glioneuronal tumor, PDGFRA p.K385-mutant: clinical, radiologic, and histopathologic features. Brain pathology (Zurich, Switzerland) Lucas, C. G., Villanueva-Meyer, J. E., Whipple, N., Oberheim Bush, N. A., Cooney, T., Chang, S., McDermott, M., Berger, M., Cham, E., Sun, P. P., Putnam, A., Zhou, H., Bollo, R., Cheshier, S., Poppe, M. M., Fung, K. M., Sung, S., Glenn, C., Fan, X., Bannykh, S., Hu, J., Danielpour, M., Li, R., Alva, E., Johnston, J., Van Ziffle, J., Onodera, C., Devine, P., Grenert, J. P., Lee, J. C., Pekmezci, M., Tihan, T., Bollen, A. W., Perry, A., Solomon, D. A. 2020; 30 (3): 479-494

  Abstract

  "Myxoid glioneuronal tumor, PDGFRA p.K385-mutant" is a recently described tumor entity of the central nervous system with a predilection for origin in the septum pellucidum and a defining dinucleotide mutation at codon 385 of the PDGFRA oncogene replacing lysine with either leucine or isoleucine (p.K385L/I). Clinical outcomes and optimal treatment for this new tumor entity have yet to be defined. Here, we report a comprehensive clinical, radiologic, and histopathologic assessment of eight cases. In addition to its stereotypic location in the septum pellucidum, we identify that this tumor can also occur in the corpus callosum and periventricular white matter of the lateral ventricle. Tumors centered in the septum pellucidum uniformly were associated with obstructive hydrocephalus, whereas tumors centered in the corpus callosum and periventricular white matter did not demonstrate hydrocephalus. While multiple patients were found to have ventricular dissemination or local recurrence/progression, all patients in this series remain alive at last clinical follow-up despite only biopsy or subtotal resection without adjuvant therapy in most cases. Our study further supports "myxoid glioneuronal tumor, PDGFRA p.K385-mutant" as a distinct CNS tumor entity and expands the spectrum of clinicopathologic and radiologic features of this neoplasm.

  View details for DOI 10.1111/bpa.12797

  View details for PubMedID 31609499

  View details for PubMedCentralID PMC7780370

• An update on the central nervous system manifestations of familial tumor predisposition syndromes. Acta neuropathologica Solomon, D. A. 2020; 139 (4): 609-612

  View details for DOI 10.1007/s00401-020-02130-0

  View details for PubMedID 32016553

  View details for PubMedCentralID PMC7102922

• Catastrophic stroke burden in a patient with uncontrolled psoriasis and psoriatic arthritis: a case report. BMC neurology Fan, J. M., Solomon, D. A., López, G. Y., Hofmann, J. W., Colorado, R. A., Kim, A. S., Meisel, K., Halabi, C. 2020; 20 (1): 106

  Abstract

  Psoriasis is the most common chronic inflammatory condition involving the T helper cell system. Population studies have demonstrated that patients with psoriasis and/or psoriatic arthritis have an increased risk of developing vascular risk factors, including diabetes, hypertension, and obesity, and increased risk of adverse vascular events, including myocardial infarction and stroke. Population studies have generally investigated the individual contributions of psoriasis and psoriatic arthritis to development of vascular risk factors; fewer studies have investigated the additive contribution of comorbid inflammatory disorders. We present a case of a woman with psoriasis, psoriatic arthritis, and comorbid vascular risk factors.A 49 year-old Caucasian woman with a history of severe psoriasis and psoriatic arthritis since adolescence presented with bilateral lower extremity weakness. She was found to have acute bilateral watershed infarcts and multifocal subacute infarcts. Her evaluation revealed vascular risk factors and elevated non-specific systemic inflammatory markers; serum and cerebral spinal fluid did not reveal underlying infection, hypercoagulable state, or vasculitis. Over the course of days, she exhibited precipitous clinical deterioration related to multiple large vessel occlusions, including the bilateral anterior cerebral arteries and the left middle cerebral artery. Autopsy revealed acute thrombi and diffuse, severe atherosclerosis.Patients with early onset inflammatory disease activity or comorbid inflammatory disorders may have an even higher risk of developing metabolic syndrome and adverse vascular events compared to patients with late-onset disease activity or with a single inflammatory condition. The described case illustrates the complex relationship between inflammatory disorders and vascular risk factors. The degree of systemic inflammation, as measured by severity of disease activity, has been shown to have a dose-response relationship with comorbid vascular risk factors and vascular events. Dysregulation of the Th1 and Th17 system has been implicated in the development of atherosclerosis and may explain the severe atherosclerosis seen in such chronic inflammatory conditions. Further research will help refine screening and management guidelines to account for comorbid inflammatory disorders and related disease severity.

  View details for DOI 10.1186/s12883-020-01681-9

  View details for PubMedID 32199449

  View details for PubMedCentralID PMC7085172

• Loss of H3K27 trimethylation by immunohistochemistry is frequent in oligodendroglioma, IDH-mutant and 1p/19q-codeleted, but is neither a sensitive nor a specific marker. Acta neuropathologica Pekmezci, M., Phillips, J. J., Dirilenoglu, F., Atasever-Rezanko, T., Tihan, T., Solomon, D., Bollen, A., Perry, A. 2020; 139 (3): 597-600

  View details for DOI 10.1007/s00401-019-02123-8

  View details for PubMedID 31912209

• Clinicopathologic and molecular features of intracranial desmoplastic small round cell tumors. Brain pathology (Zurich, Switzerland) Lee, J. C., Villanueva-Meyer, J. E., Ferris, S. P., Cham, E. M., Zucker, J., Cooney, T., Gilani, A., Kleinschmidt-DeMasters, B. K., Trembath, D., Mafra, M., Chiang, J., Ellison, D. W., Cho, S. J., Horvai, A. E., Van Ziffle, J., Onodera, C., Devine, P., Grenert, J. P., de Voijs, C. M., van Blokland, W. T., de Leng, W. W., Ploegmakers, M. J., Flucke, U., Pekmezci, M., Bollen, A. W., Tihan, T., Koelsche, C., von Deimling, A., Wesseling, P., Solomon, D. A., Perry, A. 2020; 30 (2): 213-225

  Abstract

  Desmoplastic small round cell tumors (DSRCTs) are highly aggressive sarcomas that most commonly occur intra-abdominally, and are defined by EWSR1-WT1 gene fusion. Intracranial DSRCTs are exceptionally rare with only seven previously reported fusion-positive cases. Herein, we evaluate the clinical, morphologic, immunohistochemical and molecular features of five additional examples. All patients were male (age range 6-25 years; median 11 years), with four tumors located supratentorially and one within the posterior fossa. The histologic features were highly variable including small cell, embryonal, clear cell, rhabdoid, anaplastic and glioma-like appearances. A prominent desmoplastic stroma was seen in only two cases. The mitotic index ranged from <1 to 12/10 HPF (median 5). While all tumors showed strong desmin positivity, epithelial markers such as EMA, CAM 5.2 and other keratins were strongly positive in only one, focally positive in two and negative in two cases. EWSR1-WT1 gene fusion was present in all cases, with accompanying mutations in the TERT promoter or STAG2 gene in individual cases. Given the significant histologic diversity, in the absence of genetic evaluation these cases could easily be misinterpreted as other entities. Desmin immunostaining is a useful initial screening method for consideration of a DSRCT diagnosis, prompting confirmatory molecular testing. Demonstrating the presence of an EWSR1-WT1 fusion provides a definitive diagnosis of DSRCT. Genome-wide methylation profiles of intracranial DSRCTs matched those of extracranial DSRCTs. Thus, despite the occasionally unusual histologic features and immunoprofile, intracranial DSRCTs likely represent a similar, if not the same, entity as their soft tissue counterpart based on the shared fusion and methylation profiles.

  View details for DOI 10.1111/bpa.12809

  View details for PubMedID 31837177

  View details for PubMedCentralID PMC7780368

• A review of recently described genetic alterations in central nervous system tumors. Human pathology Lucas, C. G., Solomon, D. A., Perry, A. 2020; 96: 56-66

  Abstract

  Advances in molecular profiling of central nervous system tumors have enabled the development of classification schemes with improved diagnostic and prognostic accuracy. As such, the 2016 World Health Organization Classification of Tumors of the Central Nervous System (WHO 2016) introduced a paradigm shift in the diagnosis of brain tumors. For instance, integrated assessment incorporating both histologic features and genetic alterations was introduced into the diagnostic framework of gliomas. IDH1/2 mutation status now represents the most important initial stratifier of diffuse gliomas in adults, although rarer subtypes within the IDH-wildtype category continue to be elucidated. Medulloblastomas and other embryonal neoplasms were also genetically defined and segregated based on molecular subtypes, and 1 molecular subtype of ependymoma was added. In this review, we summarize the rapidly evolving spectrum of recurrent genetic alterations described in central nervous system tumor entities since the publication of the WHO 2016.

  View details for DOI 10.1016/j.humpath.2019.10.009

  View details for PubMedID 31678207

• High-grade neuroepithelial tumor with BCOR exon 15 internal tandem duplication-a comprehensive clinical, radiographic, pathologic, and genomic analysis. Brain pathology (Zurich, Switzerland) Ferris, S. P., Velazquez Vega, J., Aboian, M., Lee, J. C., Van Ziffle, J., Onodera, C., Grenert, J. P., Saunders, T., Chen, Y. Y., Banerjee, A., Kline, C. N., Gupta, N., Raffel, C., Samuel, D., Ruiz-Diaz, I., Magaki, S., Wilson, D., Neltner, J., Al-Hajri, Z., Phillips, J. J., Pekmezci, M., Bollen, A. W., Tihan, T., Schniederjan, M., Cha, S., Perry, A., Solomon, D. A. 2020; 30 (1): 46-62

  Abstract

  High-grade neuroepithelial tumor with BCOR exon 15 internal tandem duplication (HGNET BCOR ex15 ITD) is a recently proposed tumor entity of the central nervous system (CNS) with a distinct methylation profile and characteristic genetic alteration. The complete spectrum of histologic features, accompanying genetic alterations, clinical outcomes, and optimal treatment for this new tumor entity are largely unknown. Here, we performed a comprehensive assessment of 10 new cases of HGNET BCOR ex15 ITD. The tumors mostly occurred in young children and were located in the cerebral or cerebellar hemispheres. On imaging all tumors were large, well-circumscribed, heterogeneous masses with variable enhancement and reduced diffusion. They were histologically characterized by predominantly solid growth, glioma-like fibrillarity, perivascular pseudorosettes, and palisading necrosis, but absence of microvascular proliferation. They demonstrated sparse to absent GFAP expression, no synaptophysin expression, variable OLIG2 and NeuN positivity, and diffuse strong BCOR nuclear positivity. While BCOR exon 15 internal tandem duplication was the solitary pathogenic alteration identified in six cases, four cases contained additional alterations including CDKN2A/B homozygous deletion, TERT amplification or promoter hotspot mutation, and damaging mutations in TP53, BCORL1, EP300, SMARCA2 and STAG2. While the limited clinical follow-up in prior reports had indicated a uniformly dismal prognosis for this tumor entity, this cohort includes multiple long-term survivors. Our study further supports inclusion of HGNET BCOR ex15 ITD as a distinct CNS tumor entity and expands the known clinicopathologic, radiographic, and genetic features.

  View details for DOI 10.1111/bpa.12747

  View details for PubMedID 31104347

  View details for PubMedCentralID PMC6859193

• Neuroglial stem cell-derived inflammatory pseudotumor (n-SCIPT): clinicopathologic characterization of a novel lesion of the lumbosacral spinal cord and nerve roots following intrathecal allogeneic stem cell intervention. Acta neuropathologica Sloan, E. A., Sampognaro, P. J., Junn, J. C., Chin, C., Jacques, L., Ramachandran, P. S., DeRisi, J. L., Wilson, M. R., Kriegstein, A. R., Bollen, A. W., Solomon, D. A., Margeta, M., Engstrom, J. W. 2019; 138 (6): 1103-1106

  View details for DOI 10.1007/s00401-019-02089-7

  View details for PubMedID 31659431

  View details for PubMedCentralID PMC6858593

• Recurrent non-canonical histone H3 mutations in spinal cord diffuse gliomas. Acta neuropathologica Sloan, E. A., Cooney, T., Oberheim Bush, N. A., Buerki, R., Taylor, J., Clarke, J. L., Torkildson, J., Kline, C., Reddy, A., Mueller, S., Banerjee, A., Butowski, N., Chang, S., Mummaneni, P. V., Chou, D., Tan, L., Theodosopoulos, P., McDermott, M., Berger, M., Raffel, C., Gupta, N., Sun, P. P., Li, Y., Shah, V., Cha, S., Braunstein, S., Raleigh, D. R., Samuel, D., Scharnhorst, D., Fata, C., Guo, H., Moes, G., Kim, J. Y., Koschmann, C., Van Ziffle, J., Onodera, C., Devine, P., Grenert, J. P., Lee, J. C., Pekmezci, M., Phillips, J. J., Tihan, T., Bollen, A. W., Perry, A., Solomon, D. A. 2019; 138 (5): 877-881

  View details for DOI 10.1007/s00401-019-02072-2

  View details for PubMedID 31515627

  View details for PubMedCentralID PMC6818961

• A case of recurrent epilepsy-associated rosette-forming glioneuronal tumor with anaplastic transformation in the absence of therapy. Neuropathology : official journal of the Japanese Society of Neuropathology Halfpenny, A., Ferris, S. P., Grafe, M., Woltjer, R., Selden, N., Nazemi, K., Perry, A., Solomon, D. A., Gultekin, S. H., Moore, S., Olson, S., Lawce, H., Lucas, L., Corless, C. L., Wood, M. D. 2019; 39 (5): 389-393

  Abstract

  Rosette-forming glioneuronal tumor (RGNT) most commonly occurs adjacent to the fourth ventricle and therefore rarely presents with epilepsy. Recent reports describe RGNT occurrence in other anatomical locations with considerable morphologic and genetic overlap with the epilepsy-associated dysembryoplastic neuroepithelial tumor (DNET). Examples of RGNT or DNET with anaplastic change are rare, and typically occur in the setting of radiation treatment. We present the case of a 5-year-old girl with seizures, who underwent near total resection of a cystic temporal lobe lesion. Pathology showed morphologic and immunohistochemical features of RGNT, albeit with focally overlapping DNET-like patterns. Resections of residual or recurrent tumor were performed 1 year and 5 years after the initial resection, but no adjuvant radiation or chemotherapy was given. Ten years after the initial resection, surveillance imaging identified new and enhancing nodules, leading to another gross total resection. This specimen showed areas similar to the original tumor, but also high-grade foci with oligodendroglial morphology, increased cellularity, palisading necrosis, microvascular proliferation, and up to 13 mitotic figures per 10 high power fields. Ancillary studies the status by sequencing showed wild-type of the isocitrate dehydrogenase 1 (IDH1), IDH2, and human histone 3.3 (H3F3A) genes, and BRAF studies were negative for mutation or rearrangement. Fluorescence in situ hybridization (FISH) showed codeletion of 1p and 19q limited to the high-grade regions. By immunohistochemistry there was loss of nuclear alpha-thalassemia mental retardation syndrome, X-linked (ATRX) expression only in the high-grade region. Next-generation sequencing showed an fibroblast growth factor receptor receptor 1 (FGFR1) kinase domain internal tandem duplication in three resection specimens. ATRX mutation in the high-grade tumor was confirmed by sequencing which showed a frameshift mutation (p.R1427fs), while the apparent 1p/19q-codeletion by FISH was due to loss of chromosome arm 1p and only partial loss of 19q. Exceptional features of this case include the temporal lobe location, 1p/19q loss by FISH without true whole-arm codeletion, and anaplastic transformation associated with ATRX mutation without radiation or chemotherapy.

  View details for DOI 10.1111/neup.12586

  View details for PubMedID 31435988

  View details for PubMedCentralID PMC6852525

• Loss of ZNF750 in ocular and cutaneous sebaceous carcinoma. Journal of cutaneous pathology North, J. P., Solomon, D. A., Golovato, J., Bloomer, M., Benz, S. C., Cho, R. J. 2019; 46 (10): 736-741

  Abstract

  Sebaceous carcinoma (SeC) is an uncommon malignancy arising from sebaceous glands of the conjunctiva and skin. Recurrent mutations in the ZNF750 were recently identified in ocular SeC. We assessed whether ZNF750 loss is a specific feature of ocular SeC or a general feature of sebaceous tumors.Immunostaining for ZNF750 expression was performed in 54 benign and malignant sebocytic proliferations. Staining for ZNF750 was scored on a three-tier scale: positive (>75%), partially positive (5%-74%), and negative (<5%).ZNF750 expression was negative in 4/11 ocular SeC, and partially positive in 4/11 ocular SeC and 6/13 cutaneous SeC. No extraocular tumors were negative. No loss was found in sebaceous adenoma or sebaceous hyperplasia. In nine previously sequenced ocular SeCs, two lacked detectable somatic mutations in ZNF750, but showed complete loss of staining, indicating non-mutational inactivation of ZNF750.We show complete loss of the ZNF750 epidermal differentiation regulator in about half of ocular SeC, highlighting the most common genetic defect in this cancer type. Loss of ZNF750 expression is seen even in tumors without truncating mutations and reduced in many of the remaining ocular and cutaneous SeC. In contrast, no ZNF750 loss was detected in benign sebaceous proliferations.

  View details for DOI 10.1111/cup.13516

  View details for PubMedID 31148199

  View details for PubMedCentralID PMC6744339

• ALK-positive histiocytosis with KIF5B-ALK fusion in the central nervous system. Acta neuropathologica Lucas, C. G., Gilani, A., Solomon, D. A., Liang, X., Maher, O. M., Chamyan, G., Kleinschmidt-Demasters, B. K., Perry, A. 2019; 138 (2): 335-337

  View details for DOI 10.1007/s00401-019-02027-7

  View details for PubMedID 31119374

  View details for PubMedCentralID PMC6712982

• An unusual recurrent high-grade glioneuronal tumor with MAP2K1 mutation and CDKN2A/B homozygous deletion ACTA NEUROPATHOLOGICA COMMUNICATIONS Cheaney, B., Bowden, S., Krause, K., Sloan, E. A., Perry, A., Solomon, D. A., Han, S., Wood, M. D. 2019; 7: 110

  View details for DOI 10.1186/s40478-019-0763-x

  View details for Web of Science ID 000475520800001

  View details for PubMedID 31288852

  View details for PubMedCentralID PMC6617605

• Fertility treatment is associated with multiple meningiomas and younger age at diagnosis. Journal of neuro-oncology Shahin, M. N., Magill, S. T., Dalle Ore, C. L., Viner, J. A., Peters, P. N., Solomon, D. A., McDermott, M. W. 2019; 143 (1): 137-144

  Abstract

  Meningiomas are more common in females and 70-80% express the progesterone receptor, raising the possibility that high-dose exogenous estrogen/progesterone exposure, such as occurs during fertility treatments, may increase the risk of developing a meningioma. The goal of this study was to report the incidence of prior fertility treatment in a consecutive series of female meningioma patients.A retrospective review (2015-2018) was performed of female patients with meningioma, and those with prior fertility treatment were compared to those without fertility treatment using standard statistical methods.Of 206 female patients with meningioma, 26 (12.6%) had a history of fertility treatments. Patients underwent various forms of assisted reproductive technology including: in vitro fertilization (50.0%), clomiphene with or without intrauterine insemination (34.6%), and unspecified (19.2%). Median follow up was 1.8 years. Tumors were WHO grade I (78.6%) or grade II (21.4%). Patients who underwent fertility treatments presented at significantly younger mean age compared to those who had not (51.8 vs. 57.3 years, p = 0.0135, 2-tailed T-test), and on multivariate analysis were more likely to have multiple meningiomas (OR 4.97, 95% CI 1.4-18.1, p = 0.0154) and convexity/falx meningiomas (OR 4.45, 95% CI 1.7-11.5, p = 0.0021).Patients in this cohort with a history of fertility treatment were more likely to present at a younger age and have multiple and convexity/falx meningiomas, emphasizing the importance of taking estrogen/progesterone exposure history when evaluating patients with meningioma. Future clinical studies at other centers in larger populations and laboratory investigations are needed to determine the role of fertility treatment in meningioma development.

  View details for DOI 10.1007/s11060-019-03147-6

  View details for PubMedID 30868355

  View details for PubMedCentralID PMC6486831

• Recurrent EP300-BCOR Fusions in Pediatric Gliomas With Distinct Clinicopathologic Features. Journal of neuropathology and experimental neurology Torre, M., Meredith, D. M., Dubuc, A., Solomon, D. A., Perry, A., Vasudevaraja, V., Serrano, J., Snuderl, M., Ligon, K. L., Alexandrescu, S. 2019; 78 (4): 305-314

  Abstract

  BCOR is an epigenetic regulator and is genetically altered by mutation, deletion, or gene fusion in a range of cancers. "Central nervous system high-grade neuroepithelial tumor with BCOR alteration" is a recently described entity with characteristic internal tandem duplications within exon 15 of the BCOR gene (hereafter: CNS HGNET-BCOR ex15 ITD). In this case series of 3 patients, we report the clinicopathologic, molecular, and methylome features of gliomas with novel EP300-BCOR in-frame gene fusions, thus expanding the spectrum of BCOR alterations seen in CNS tumors. The gliomas in this series arise in children (ages 10-18), involve the supratentorial compartment, and have an infiltrative pattern of growth and a myxoid/microcystic background with frequent psammomatous calcifications and prominent chicken-wire vessels. All 3 cases had areas with low-grade morphology and 2 of them demonstrated histologic high-grade transformation. In contrast to CNS HGNET-BCOR ex15 ITD, they lack perivascular pseudorosettes. On a t-Distributed Stochastic Neighbor Embedding plot they cluster perfectly together, away from CNS HGNET-BCOR ex15ITD, consistent with a different entity. Gliomas with EP300-BCOR fusions and high-grade histology can demonstrate relatively rapid regrowth after debulking or subtotal resection.

  View details for DOI 10.1093/jnen/nlz011

  View details for PubMedID 30816933

• A pilot precision medicine trial for children with diffuse intrinsic pontine glioma-PNOC003: A report from the Pacific Pediatric Neuro-Oncology Consortium. International journal of cancer Mueller, S., Jain, P., Liang, W. S., Kilburn, L., Kline, C., Gupta, N., Panditharatna, E., Magge, S. N., Zhang, B., Zhu, Y., Crawford, J. R., Banerjee, A., Nazemi, K., Packer, R. J., Petritsch, C. K., Truffaux, N., Roos, A., Nasser, S., Phillips, J. J., Solomon, D., Molinaro, A., Waanders, A. J., Byron, S. A., Berens, M. E., Kuhn, J., Nazarian, J., Prados, M., Resnick, A. C. 2019

  Abstract

  This clinical trial evaluated whether whole exome sequencing (WES) and RNA sequencing (RNAseq) of paired normal and tumor tissues could be incorporated into a personalized treatment plan for newly diagnosed patients (<25 years of age) with diffuse intrinsic pontine glioma (DIPG). Additionally, whole genome sequencing (WGS) was compared to WES to determine if WGS would further inform treatment decisions, and whether circulating tumor DNA (ctDNA) could detect the H3K27M mutation to allow assessment of therapy response. Patients were selected across three Pacific Pediatric Neuro-Oncology Consortium member institutions between September 2014 and January 2016. WES and RNAseq were performed at diagnosis and recurrence when possible in a CLIA-certified laboratory. Patient-derived cell line development was attempted for each subject. Collection of blood for ctDNA was done prior to treatment and with each MRI. A specialized tumor board generated a treatment recommendation including up to four FDA-approved agents based upon the genomic alterations detected. A treatment plan was successfully issued within 21 business days from tissue collection for all 15 subjects, with 14 of the 15 subjects fulfilling the feasibility criteria. WGS results did not significantly deviate from WES-based therapy recommendations; however, WGS data provided further insight into tumor evolution and fidelity of patient-derived cell models. Detection of the H3F3A or HIST1H3B K27M (H3K27M) mutation using ctDNA was successful in 92% of H3K27M mutant cases. A personalized treatment recommendation for DIPG can be rendered within a multicenter setting using comprehensive next-generation sequencing technology in a clinically relevant timeframe.

  View details for DOI 10.1002/ijc.32258

  View details for PubMedID 30861105

• Primary intracranial sarcomas with DICER1 mutation often contain prominent eosinophilic cytoplasmic globules and can occur in the setting of neurofibromatosis type 1. Acta neuropathologica Lee, J. C., Villanueva-Meyer, J. E., Ferris, S. P., Sloan, E. A., Hofmann, J. W., Hattab, E. M., Williams, B. J., Guo, H., Torkildson, J., Florez, A., Van Ziffle, J., Onodera, C., Grenert, J. P., Cho, S. J., Horvai, A. E., Jones, D. T., Pfister, S. M., Koelsche, C., von Deimling, A., Korshunov, A., Perry, A., Solomon, D. A. 2019; 137 (3): 521-525

  View details for DOI 10.1007/s00401-019-01960-x

  View details for PubMedID 30649606

  View details for PubMedCentralID PMC6408274

• CRTC1-MAML2 fusion in mucoepidermoid carcinoma of the breast HISTOPATHOLOGY Bean, G. R., Krings, G., Otis, C. N., Solomon, D. A., Garcia, J. J., van Zante, A., Camelo-Piragua, S., van Ziffle, J., Chen, Y. 2019; 74 (3): 463–73

  View details for DOI 10.1111/his.13779

  View details for Web of Science ID 000459597000010

• Clinicopathologic features of anaplastic myxopapillary ependymomas. Brain pathology (Zurich, Switzerland) Lee, J. C., Sharifai, N., Dahiya, S., Kleinschmidt-DeMasters, B. K., Rosenblum, M. K., Reis, G. F., Samuel, D., Siongco, A. M., Santi, M., Storm, P. B., Ferris, S. P., Bollen, A. W., Pekmezci, M., Solomon, D. A., Tihan, T., Perry, A. 2019; 29 (1): 75-84

  Abstract

  Myxopapillary ependymomas (MPE) are considered benign (World Health Organization (WHO) grade I) neoplasms with favorable prognosis. However, malignant behavior occurs in a small subset. To our knowledge, only five anaplastic MPEs have been reported without consensus on diagnostic criteria. We retrieved 14 anaplastic MPEs from the pathology archives of six institutions. Each tumor included at least two of the following features: ≥5 mitoses per 10 high power fields, Ki-67 labeling index (LI) ≥10%, microvascular proliferation (MVP) and spontaneous necrosis. These features were typically encountered in the foci of hypercellularity and reduced mucin. There were eight male and six female patients (age range 6-57 years, median = 16.5). Ten tumors displayed anaplasia at initial resection, and 4 were anaplastic at a second surgery for recurrence (ranging from 9 months to 14 years following initial resection). The Ki-67 LI ranged between 8% and 40% in the anaplastic foci and <3% in the foci of classic MPE. There was documented cerebrospinal fluid (CSF) dissemination in seven cases, recurrence following an anaplastic diagnosis in three cases and bone or soft tissue invasion in two cases. One patient suffered lung metastases. Two cases evaluated by targeted next-generation sequencing and one evaluated by fluorescence in situ hybridization (FISH) showed nonspecific chromosomal gains. We conclude that although rare, anaplastic MPE occurs in both pediatric and adult patients, similar to other ependymomas. At a minimum, closer follow-up is recommended, given the concern for aggressive biologic potential. Further study is needed to determine WHO grading criteria and genetic indicators of tumor progression.

  View details for DOI 10.1111/bpa.12673

  View details for PubMedID 30417460

  View details for PubMedCentralID PMC7444646

• The genetic landscape of anaplastic pleomorphic xanthoastrocytoma. Brain pathology (Zurich, Switzerland) Phillips, J. J., Gong, H., Chen, K., Joseph, N. M., van Ziffle, J., Bastian, B. C., Grenert, J. P., Kline, C. N., Mueller, S., Banerjee, A., Nicolaides, T., Gupta, N., Berger, M. S., Lee, H. S., Pekmezci, M., Tihan, T., Bollen, A. W., Perry, A., Shieh, J. T., Solomon, D. A. 2019; 29 (1): 85-96

  Abstract

  Pleomorphic xanthoastrocytoma (PXA) is an astrocytic neoplasm that is typically well circumscribed and can have a relatively favorable prognosis. Tumor progression to anaplastic PXA (WHO grade III), however, is associated with a more aggressive biologic behavior and worse prognosis. The factors that drive anaplastic progression are largely unknown. We performed comprehensive genomic profiling on a set of 23 PXAs from 19 patients, including 15 with anaplastic PXA. Four patients had tumor tissue from multiple recurrences, including two with anaplastic progression. We find that PXAs are genetically defined by the combination of CDKN2A biallelic inactivation and RAF alterations that were present in all 19 cases, most commonly as CDKN2A homozygous deletion and BRAF p.V600E mutation but also occasionally BRAF or RAF1 fusions or other rearrangements. The third most commonly altered gene in anaplastic PXA was TERT, with 47% (7/15) harboring TERT alterations, either gene amplification (n = 2) or promoter hotspot mutation (n = 5). In tumor pairs analyzed before and after anaplastic progression, two had increased copy number alterations and one had TERT promoter mutation at recurrence. Less commonly altered genes included TP53, BCOR, BCORL1, ARID1A, ATRX, PTEN, and BCL6. All PXA in this cohort were IDH and histone H3 wildtype, and did not contain alterations in EGFR. Genetic profiling performed on six regions from the same tumor identified intratumoral genomic heterogeneity, likely reflecting clonal evolution during tumor progression. Overall, anaplastic PXA is characterized by the combination of CDKN2A biallelic inactivation and oncogenic RAF kinase signaling as well as a relatively small number of additional genetic alterations, with the most common being TERT amplification or promoter mutation. These data define a distinct molecular profile for PXA and suggest additional genetic alterations, including TERT, may be associated with anaplastic progression.

  View details for DOI 10.1111/bpa.12639

  View details for PubMedID 30051528

  View details for PubMedCentralID PMC7837273

• Early detection of recurrent medulloblastoma: the critical role of diffusion-weighted imaging. Neuro-oncology practice Aboian, M. S., Kline, C. N., Li, Y., Solomon, D. A., Felton, E., Banerjee, A., Braunstein, S. E., Mueller, S., Dillon, W. P., Cha, S. 2018; 5 (4): 234-240

  Abstract

  Imaging diagnosis of medulloblastoma recurrence relies heavily on identifying new contrast-enhancing lesions on surveillance imaging, with diffusion-weighted imaging (DWI) being used primarily for detection of complications. We propose that DWI is more sensitive in detecting distal and leptomeningeal recurrent medulloblastoma than T1-weighted postgadolinium imaging.We identified 53 pediatric patients with medulloblastoma, 21 of whom developed definitive disease recurrence within the brain. MRI at diagnosis of recurrence and 6 months prior was evaluated for new lesions with reduced diffusion on DWI, contrast enhancement, size, and recurrence location.All recurrent medulloblastoma lesions demonstrated reduced diffusion. Apparent diffusion coefficient (ADC) measurements were statistically significantly lower (P = .00001) in recurrent lesions (mean=0.658, SD=0.072) as compared to contralateral normal region of interest (mean=0.923, SD=0.146). Sixteen patients (76.2%) with disease recurrence demonstrated contrast enhancement within the recurrent lesions. All 5 patients with nonenhancing recurrence demonstrated reduced diffusion, with a mean ADC of 0.695 ± 0.101 (normal=0.893 ± 0.100, P = .0027). While group 3 and group 4 molecular subtypes demonstrated distal recurrence more frequently, nonenhancing metastatic disease was found in all molecular subtypes.Recurrent medulloblastoma lesions do not uniformly demonstrate contrast enhancement on MRI, but all demonstrate reduced diffusion. Our findings support that DWI is more sensitive than contrast enhancement for detection of medulloblastoma recurrence, particularly in cases of leptomeningeal nonenhancing disease and distal nonenhancing focal disease. As such, recurrent medulloblastoma can present as a reduced diffusion lesion in a patient with normal postgadolinium contrast MRI.

  View details for DOI 10.1093/nop/npx036

  View details for PubMedID 30402262

  View details for PubMedCentralID PMC6213943

• Oligodendrogliomas, IDH-mutant and 1p/19q-codeleted, arising during teenage years often lack TERT promoter mutation that is typical of their adult counterparts. Acta neuropathologica communications Lee, J., Putnam, A. R., Chesier, S. H., Banerjee, A., Raffel, C., Van Ziffle, J., Onodera, C., Grenert, J. P., Bastian, B. C., Perry, A., Solomon, D. A. 2018; 6 (1): 95

  View details for DOI 10.1186/s40478-018-0598-x

  View details for PubMedID 30231927

  View details for PubMedCentralID PMC6145350

• STAG2 Is a Biomarker for Prediction of Recurrence and Progression in Papillary Non-Muscle-Invasive Bladder Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research Lelo, A., Prip, F., Harris, B. T., Solomon, D., Berry, D. L., Chaldekas, K., Kumar, A., Simko, J., Jensen, J. B., Bhattacharyya, P., Mannion, C., Kim, J. S., Philips, G., Dyrskjøt, L., Waldman, T. 2018; 24 (17): 4145-4153

  Abstract

  Purpose: Most bladder cancers are early-stage tumors known as papillary non-muscle-invasive bladder cancer (NMIBC). After resection, up to 70% of NMIBCs recur locally, and up to 20% of these recurrences progress to muscle invasion. There is an unmet need for additional biomarkers for stratifying tumors based on their risk of recurrence and progression. We previously identified STAG2 as among the most commonly mutated genes in NMIBC and provided initial evidence in a pilot cohort that STAG2-mutant tumors recurred less frequently than STAG2 wild-type tumors. Here, we report a STAG2 biomarker validation study using two independent cohorts of clinically annotated papillary NMIBC tumors from the United States and Europe.Experimental Design: The value of STAG2 immunostaining for prediction of recurrence was initially evaluated in a cohort of 82 patients with papillary NMIBC ("Georgetown cohort"). Next, the value of STAG2 immunostaining for prediction of progression to muscle invasion was evaluated in a progressor-enriched cohort of 253 patients with papillary NMIBC ("Aarhus cohort").Results: In the Georgetown cohort, 52% of NMIBC tumors with intact STAG2 expression recurred, whereas 25% of STAG2-deficient tumors recurred (P = 0.02). Multivariable analysis identified intact STAG2 expression as an independent predictor of recurrence (HR = 2.4; P = 0.05). In the progressor-enriched Aarhus cohort, 38% of tumors with intact STAG2 expression progressed within 5 years, versus 16% of STAG2-deficient tumors (P < 0.01). Multivariable analysis identified intact STAG2 expression as an independent predictor of progression (HR = 1.86; P = 0.05).Conclusions: STAG2 IHC is a simple, binary, new assay for risk stratification in papillary NMIBC. Clin Cancer Res; 24(17); 4145-53. ©2018 AACR.

  View details for DOI 10.1158/1078-0432.CCR-17-3244

  View details for PubMedID 29954776

  View details for PubMedCentralID PMC6125225

• The genetic landscape of ganglioglioma. Acta neuropathologica communications Pekmezci, M., Villanueva-Meyer, J. E., Goode, B., Van Ziffle, J., Onodera, C., Grenert, J. P., Bastian, B. C., Chamyan, G., Maher, O. M., Khatib, Z., Kleinschmidt-DeMasters, B. K., Samuel, D., Mueller, S., Banerjee, A., Clarke, J. L., Cooney, T., Torkildson, J., Gupta, N., Theodosopoulos, P., Chang, E. F., Berger, M., Bollen, A. W., Perry, A., Tihan, T., Solomon, D. A. 2018; 6 (1): 47

  Abstract

  Ganglioglioma is the most common epilepsy-associated neoplasm that accounts for approximately 2% of all primary brain tumors. While a subset of gangliogliomas are known to harbor the activating p.V600E mutation in the BRAF oncogene, the genetic alterations responsible for the remainder are largely unknown, as is the spectrum of any additional cooperating gene mutations or copy number alterations. We performed targeted next-generation sequencing that provides comprehensive assessment of mutations, gene fusions, and copy number alterations on a cohort of 40 gangliogliomas. Thirty-six harbored mutations predicted to activate the MAP kinase signaling pathway, including 18 with BRAF p.V600E mutation, 5 with variant BRAF mutation (including 4 cases with novel in-frame insertions at p.R506 in the β3-αC loop of the kinase domain), 4 with BRAF fusion, 2 with KRAS mutation, 1 with RAF1 fusion, 1 with biallelic NF1 mutation, and 5 with FGFR1/2 alterations. Three gangliogliomas with BRAF p.V600E mutation had concurrent CDKN2A homozygous deletion and one additionally harbored a subclonal mutation in PTEN. Otherwise, no additional pathogenic mutations, fusions, amplifications, or deletions were identified in any of the other tumors. Amongst the 4 gangliogliomas without canonical MAP kinase pathway alterations identified, one epilepsy-associated tumor in the temporal lobe of a young child was found to harbor a novel ABL2-GAB2 gene fusion. The underlying genetic alterations did not show significant association with patient age or disease progression/recurrence in this cohort. Together, this study highlights that ganglioglioma is characterized by genetic alterations that activate the MAP kinase pathway, with only a small subset of cases that harbor additional pathogenic alterations such as CDKN2A deletion.

  View details for DOI 10.1186/s40478-018-0551-z

  View details for PubMedID 29880043

  View details for PubMedCentralID PMC5992851

• Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort LANCET ONCOLOGY Waszak, S. M., Northcott, P. A., Buchhalter, I., Robinson, G. W., Sutter, C., Groebner, S., Grund, K. B., Brugieres, L., Jones, D. W., Pajtler, K. W., Morrissy, A., Kool, M., Sturm, D., Chavez, L., Ernst, A., Brabetz, S., Hain, M., Zichner, T., Segura-Wang, M., Weischenfeldt, J., Rausch, T., Mardin, B. R., Zhou, X., Baciu, C., Lawerenz, C., Chan, J. A., Varlet, P., Guerrini-Rousseau, L., Fults, D. W., Grajkowska, W., Hauser, P., Jabado, N., Ra, Y., Zitterbart, K., Shringarpure, S. S., De La Vega, F. M., Bustamante, C. D., Ng, H., Perry, A., MacDonald, T. J., Driever, P., Bendel, A. E., Bowers, D. C., McCowage, G., Chintagumpala, M. M., Cohn, R., Hassall, T., Fleischhack, G., Eggen, T., Wesenberg, F., Feychting, M., Lannering, B., Schuz, J., Johansen, C., Andersen, T. V., Roosli, M., Kuehni, C. E., Grotzer, M., Kjaerheim, K., Monoranu, C. M., Archer, T. C., Duke, E., Pomeroy, S. L., Shelagh, R., Frank, S., Sumerauer, D., Scheurlen, W., Ryzhova, M. V., Milde, T., Kratz, C. P., Samuel, D., Zhang, J., Solomon, D. A., Marra, M., Eils, R., Bartram, C. R., von Hoff, K., Rutkowski, S., Ramaswamy, V., Gilbertson, R. J., Korshunov, A., Taylor, M. D., Lichter, P., Malkin, D., Gajjar, A., Korbel, J. O., Pfister, S. M. 2018; 19 (6): 785–98

  Abstract

  Medulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines.In this international, multicentre study, we analysed patients with medulloblastoma from retrospective cohorts (International Cancer Genome Consortium [ICGC] PedBrain, Medulloblastoma Advanced Genomics International Consortium [MAGIC], and the CEFALO series) and from prospective cohorts from four clinical studies (SJMB03, SJMB12, SJYC07, and I-HIT-MED). Whole-genome sequences and exome sequences from blood and tumour samples were analysed for rare damaging germline mutations in cancer predisposition genes. DNA methylation profiling was done to determine consensus molecular subgroups: WNT (MBWNT), SHH (MBSHH), group 3 (MBGroup3), and group 4 (MBGroup4). Medulloblastoma predisposition genes were predicted on the basis of rare variant burden tests against controls without a cancer diagnosis from the Exome Aggregation Consortium (ExAC). Previously defined somatic mutational signatures were used to further classify medulloblastoma genomes into two groups, a clock-like group (signatures 1 and 5) and a homologous recombination repair deficiency-like group (signatures 3 and 8), and chromothripsis was investigated using previously established criteria. Progression-free survival and overall survival were modelled for patients with a genetic predisposition to medulloblastoma.We included a total of 1022 patients with medulloblastoma from the retrospective cohorts (n=673) and the four prospective studies (n=349), from whom blood samples (n=1022) and tumour samples (n=800) were analysed for germline mutations in 110 cancer predisposition genes. In our rare variant burden analysis, we compared these against 53 105 sequenced controls from ExAC and identified APC, BRCA2, PALB2, PTCH1, SUFU, and TP53 as consensus medulloblastoma predisposition genes according to our rare variant burden analysis and estimated that germline mutations accounted for 6% of medulloblastoma diagnoses in the retrospective cohort. The prevalence of genetic predispositions differed between molecular subgroups in the retrospective cohort and was highest for patients in the MBSHH subgroup (20% in the retrospective cohort). These estimates were replicated in the prospective clinical cohort (germline mutations accounted for 5% of medulloblastoma diagnoses, with the highest prevalence [14%] in the MBSHH subgroup). Patients with germline APC mutations developed MBWNT and accounted for most (five [71%] of seven) cases of MBWNT that had no somatic CTNNB1 exon 3 mutations. Patients with germline mutations in SUFU and PTCH1 mostly developed infant MBSHH. Germline TP53 mutations presented only in childhood patients in the MBSHH subgroup and explained more than half (eight [57%] of 14) of all chromothripsis events in this subgroup. Germline mutations in PALB2 and BRCA2 were observed across the MBSHH, MBGroup3, and MBGroup4 molecular subgroups and were associated with mutational signatures typical of homologous recombination repair deficiency. In patients with a genetic predisposition to medulloblastoma, 5-year progression-free survival was 52% (95% CI 40-69) and 5-year overall survival was 65% (95% CI 52-81); these survival estimates differed significantly across patients with germline mutations in different medulloblastoma predisposition genes.Genetic counselling and testing should be used as a standard-of-care procedure in patients with MBWNT and MBSHH because these patients have the highest prevalence of damaging germline mutations in known cancer predisposition genes. We propose criteria for routine genetic screening for patients with medulloblastoma based on clinical and molecular tumour characteristics.German Cancer Aid; German Federal Ministry of Education and Research; German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung); European Research Council; National Institutes of Health; Canadian Institutes for Health Research; German Cancer Research Center; St Jude Comprehensive Cancer Center; American Lebanese Syrian Associated Charities; Swiss National Science Foundation; European Molecular Biology Organization; Cancer Research UK; Hertie Foundation; Alexander and Margaret Stewart Trust; V Foundation for Cancer Research; Sontag Foundation; Musicians Against Childhood Cancer; BC Cancer Foundation; Swedish Council for Health, Working Life and Welfare; Swedish Research Council; Swedish Cancer Society; the Swedish Radiation Protection Authority; Danish Strategic Research Council; Swiss Federal Office of Public Health; Swiss Research Foundation on Mobile Communication; Masaryk University; Ministry of Health of the Czech Republic; Research Council of Norway; Genome Canada; Genome BC; Terry Fox Research Institute; Ontario Institute for Cancer Research; Pediatric Oncology Group of Ontario; The Family of Kathleen Lorette and the Clark H Smith Brain Tumour Centre; Montreal Children's Hospital Foundation; The Hospital for Sick Children: Sonia and Arthur Labatt Brain Tumour Research Centre, Chief of Research Fund, Cancer Genetics Program, Garron Family Cancer Centre, MDT's Garron Family Endowment; BC Childhood Cancer Parents Association; Cure Search Foundation; Pediatric Brain Tumor Foundation; Brainchild; and the Government of Ontario.

  View details for PubMedID 29753700

  View details for PubMedCentralID PMC5984248

• Cell of origin and mutation pattern define three clinically distinct classes of sebaceous carcinoma. Nature communications North, J. P., Golovato, J., Vaske, C. J., Sanborn, J. Z., Nguyen, A., Wu, W., Goode, B., Stevers, M., McMullen, K., Perez White, B. E., Collisson, E. A., Bloomer, M., Solomon, D. A., Benz, S. C., Cho, R. J. 2018; 9 (1): 1894

  Abstract

  Sebaceous carcinomas (SeC) are cutaneous malignancies that, in rare cases, metastasize and prove fatal. Here we report whole-exome sequencing on 32 SeC, revealing distinct mutational classes that explain both cancer ontogeny and clinical course. A UV-damage signature predominates in 10/32 samples, while nine show microsatellite instability (MSI) profiles. UV-damage SeC exhibited poorly differentiated, infiltrative histopathology compared to MSI signature SeC (p = 0.003), features previously associated with dissemination. Moreover, UV-damage SeC transcriptomes and anatomic distribution closely resemble those of cutaneous squamous cell carcinomas (SCC), implicating sun-exposed keratinocytes as a cell of origin. Like SCC, this UV-damage subclass harbors a high somatic mutation burden with >50 mutations per Mb, predicting immunotherapeutic response. In contrast, ocular SeC acquires far fewer mutations without a dominant signature, but show frequent truncations in the ZNF750 epidermal differentiation regulator. Our data exemplify how different mutational processes convergently drive histopathologically related but clinically distinct cancers.

  View details for DOI 10.1038/s41467-018-04008-y

  View details for PubMedID 29760388

  View details for PubMedCentralID PMC5951856

• STAG2 deficiency induces interferon responses via cGAS-STING pathway and restricts virus infection. Nature communications Ding, S., Diep, J., Feng, N., Ren, L., Li, B., Ooi, Y. S., Wang, X., Brulois, K. F., Yasukawa, L. L., Li, X., Kuo, C. J., Solomon, D. A., Carette, J. E., Greenberg, H. B. 2018; 9 (1): 1485

  Abstract

  Cohesin is a multi-subunit nuclear protein complex that coordinates sister chromatid separation during cell division. Highly frequent somatic mutations in genes encoding core cohesin subunits have been reported in multiple cancer types. Here, using a genome-wide CRISPR-Cas9 screening approach to identify host dependency factors and novel innate immune regulators of rotavirus (RV) infection, we demonstrate that the loss of STAG2, an important component of the cohesin complex, confers resistance to RV replication in cell culture and human intestinal enteroids. Mechanistically, STAG2 deficiency results in spontaneous genomic DNA damage and robust interferon (IFN) expression via the cGAS-STING cytosolic DNA-sensing pathway. The resultant activation of JAK-STAT signaling and IFN-stimulated gene (ISG) expression broadly protects against virus infections, including RVs. Our work highlights a previously undocumented role of the cohesin complex in regulating IFN homeostasis and identifies new therapeutic avenues for manipulating the innate immunity.

  View details for PubMedID 29662124

• Genomic analysis of the origins and evolution of multicentric diffuse lower-grade gliomas. Neuro-oncology Hayes, J., Yu, Y., Jalbert, L. E., Mazor, T., Jones, L. E., Wood, M. D., Walsh, K. M., Bengtsson, H., Hong, C., Oberndorfer, S., Roetzer, T., Smirnov, I. V., Clarke, J. L., Aghi, M. K., Chang, S. M., Nelson, S. J., Woehrer, A., Phillips, J. J., Solomon, D. A., Costello, J. F. 2018; 20 (5): 632-641

  Abstract

  Rare multicentric lower-grade gliomas (LGGs) represent a unique opportunity to study the heterogeneity among distinct tumor foci in a single patient and to infer their origins and parallel patterns of evolution.In this study, we integrate clinical features, histology, and immunohistochemistry for 4 patients with multicentric LGG, arising both synchronously and metachronously. For 3 patients we analyze the phylogeny of the lesions using exome sequencing, including one case with a total of 8 samples from the 2 lesions.One patient was diagnosed with multicentric isocitrate dehydrogenase 1 (IDH1) mutated diffuse astrocytomas harboring distinct IDH1 mutations, R132H and R132C; the latter mutation has been associated with Li-Fraumeni syndrome, which was subsequently confirmed in the patient's germline DNA and shown in additional cases with The Cancer Genome Atlas data. In another patient, phylogenetic analysis of synchronously arising grade II and grade III diffuse astrocytomas demonstrated a single shared mutation, IDH1 R132H, and revealed convergent evolution via non-overlapping mutations in ATRX and TP53. In 2 cases, there was divergent evolution of IDH1-mutated and 1p/19q-codeleted oligodendroglioma and IDH1-mutated and 1p/19q-intact diffuse astrocytoma, occurring synchronously in one case and metachronously in a second.Each tumor in multicentric LGG cases may arise independently or may diverge very early in their development, presenting as genetically and histologically distinct tumors. Comprehensive sampling of these lesions can therefore significantly alter diagnosis and management. Additionally, somatic IDH1 R132C mutation in either multicentric or solitary LGG identifies unsuspected germline TP53 mutation, validating the limited number of published cases.

  View details for DOI 10.1093/neuonc/nox205

  View details for PubMedID 29077933

  View details for PubMedCentralID PMC5892142

• Deep sequencing of WNT-activated medulloblastomas reveals secondary SHH pathway activation. Acta neuropathologica Iorgulescu, J. B., Van Ziffle, J., Stevers, M., Grenert, J. P., Bastian, B. C., Chavez, L., Stichel, D., Buchhalter, I., Samuel, D., Nicolaides, T., Banerjee, A., Mueller, S., Gupta, N., Tihan, T., Bollen, A. W., Northcott, P. A., Kool, M., Pfister, S., Korshunov, A., Perry, A., Solomon, D. A. 2018; 135 (4): 635-638

  View details for DOI 10.1007/s00401-018-1819-x

  View details for PubMedID 29435664

  View details for PubMedCentralID PMC6078208

• Multimodal molecular analysis of astroblastoma enables reclassification of most cases into more specific molecular entities. Brain pathology (Zurich, Switzerland) Wood, M. D., Tihan, T., Perry, A., Chacko, G., Turner, C., Pu, C., Payne, C., Yu, A., Bannykh, S. I., Solomon, D. A. 2018; 28 (2): 192-202

  Abstract

  Astroblastoma is a rare and controversial glioma with variable clinical behavior. The diagnosis currently rests on histologic findings of a circumscribed glioma with astroblastomatous pseudorosettes and vascular hyalinization. Immunohistochemical studies have suggested different oncogenic drivers, such as BRAF p.V600E, but very few cases have been studied using genome-wide methodologies. Recent genomic profiling identified a subset of CNS embryonal tumors with astroblastoma-like morphology that harbored MN1 gene fusions, termed "CNS high-grade neuroepithelial tumors with MN1 alteration" (CNS-HGNET-MN1). To further characterize the genetic alterations that drive astroblastomas, we performed targeted next-generation sequencing (NGS) of 500 cancer-associated genes in a series of eight cases. We correlated these findings with break-apart fluorescence in situ hybridization (FISH) analysis of the MN1 locus and genome-wide DNA methylation profiling. Four cases showed MN1 alteration by FISH, including two pediatric cases that lacked other pathogenic alterations, and two adult cases that harbored other cancer-associated gene mutations or copy number alterations (eg, CDKN2A/B homozygous deletion, TP53, ATM and TERT promoter mutations). Three of these cases grouped with the CNS-HGNET-MN1 entity by methylation profiling. Two of four MN1 intact cases by FISH showed genetic features of either anaplastic pleomorphic xanthoastrocytoma (BRAF p.V600E mutation, CDKN2A/B homozygous deletion and TERT promoter mutation) or IDH-wildtype glioblastoma (trisomy 7, monosomy 10, CDK4 amplification and TP53, NRAS and TERT promoter mutations) and these cases had an aggressive clinical course. Two clinically indolent cases remained unclassifiable despite multimodal molecular analysis. We conclude that astroblastoma histology is not specific for any entity including CNS-HGNET-MN1, and that additional genetic characterization should be considered for astroblastomas, as a number of these tumors likely contain a methylation profile or genetic alterations that suggest classification as other tumor entities. Our heterogeneous molecular findings help to explain the clinical unpredictability of astroblastoma.

  View details for DOI 10.1111/bpa.12561

  View details for PubMedID 28960623

  View details for PubMedCentralID PMC5843525

• Molecular testing for the clinical diagnosis of fibrolamellar carcinoma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc Graham, R. P., Yeh, M. M., Lam-Himlin, D., Roberts, L. R., Terracciano, L., Cruise, M. W., Greipp, P. T., Zreik, R. T., Jain, D., Zaid, N., Salaria, S. N., Jin, L., Wang, X., Rustin, J. G., Kerr, S. E., Sukov, W. R., Solomon, D. A., Kakar, S., Waterhouse, E., Gill, R. M., Ferrell, L., Alves, V. A., Nart, D., Yilmaz, F., Roessler, S., Longerich, T., Schirmacher, P., Torbenson, M. S. 2018; 31 (1): 141-149

  Abstract

  Fibrolamellar carcinoma has a distinctive morphology and immunophenotype, including cytokeratin 7 and CD68 co-expression. Despite the distinct findings, accurate diagnosis of fibrolamellar carcinoma continues to be a challenge. Recently, fibrolamellar carcinomas were found to harbor a characteristic somatic gene fusion, DNAJB1-PRKACA. A break-apart fluorescence in situ hybridization (FISH) assay was designed to detect this fusion event and to examine its diagnostic performance in a large, multicenter, multinational study. Cases initially classified as fibrolamellar carcinoma based on histological features were reviewed from 124 patients. Upon central review, 104 of the 124 cases were classified histologically as typical of fibrolamellar carcinoma, 12 cases as 'possible fibrolamellar carcinoma' and 8 cases as 'unlikely to be fibrolamellar carcinoma'. PRKACA FISH was positive for rearrangement in 102 of 103 (99%) typical fibrolamellar carcinomas, 9 of 12 'possible fibrolamellar carcinomas' and 0 of 8 cases 'unlikely to be fibrolamellar carcinomas'. Within the morphologically typical group of fibrolamellar carcinomas, two tumors with unusual FISH patterns were also identified. Both cases had the fusion gene DNAJB1-PRKACA, but one also had amplification of the fusion gene and one had heterozygous deletion of the normal PRKACA locus. In addition, 88 conventional hepatocellular carcinomas were evaluated with PRKACA FISH and all were negative. These findings demonstrate that FISH for the PRKACA rearrangement is a clinically useful tool to confirm the diagnosis of fibrolamellar carcinoma, with high sensitivity and specificity. A diagnosis of fibrolamellar carcinoma is more accurate when based on morphology plus confirmatory testing than when based on morphology alone.

  View details for DOI 10.1038/modpathol.2017.103

  View details for PubMedID 28862261

  View details for PubMedCentralID PMC5758901

• Personalized therapy: CNS HGNET-BCOR responsiveness to arsenic trioxide combined with radiotherapy. Oncotarget Paret, C., Russo, A., Otto, H., Mayer, A., Zahnreich, S., Wagner, W., Samuel, D., Scharnhorst, D., Solomon, D. A., Dhall, G., Wong, K., Bender, H., Alt, F., Wingerter, A., Neu, M. A., Beck, O., Prawitt, D., Eder, S., Henninger, N., El Malki, K., Lehmann, N., Backes, N., Roth, L., Seidmann, L., Sommer, C., Brockmann, M. A., Staatz, G., Schmidberger, H., Faber, J. 2017; 8 (69): 114210-114225

  Abstract

  High-grade neuroepithelial tumor of the central nervous system with BCOR alteration (HGNET-BCOR) is a rare, highly malignant tumor. At the time of this publication, no standard protocol exists to treat this tumor entity. In this work, we tested the responsiveness of the primary culture PhKh1 derived from tumor tissue from a pediatric HGNET-BCOR patient (P1) to inhibitors of the Sonic hedgehog pathway combined with radiation. The SMO inhibitors vismodegib and itraconazole had low effect on the proliferation of the PhKh1 cells. However, the GLI inhibitor arsenic trioxide reduced the expression of GLI target genes in the PhKh1 cells and in combination with radiotherapy significantly decreased their clonogenic potential. PhKh1 cells resistant to arsenic trioxide were characterized by the overexpression of molecular chaperones. We combined arsenic trioxide and radiation in the relapse therapy protocol of P1, achieving complete remission after seven weeks. Clinical remission lasted for six months, when P1 developed systemic metastases. Meanwhile, an increase in the concentration of circulating tumor DNA carrying a BCOR internal tandem duplication was observed. Molecular characterization of a second patient (P2) was also performed. In P2, we detected a larger tandem duplication and greater activation of the Sonic hedgehog pathway than in P1. These findings suggest that combining arsenic trioxide with radiotherapy may represent a new therapeutic approach. Moreover, peripheral blood analysis for circulating tumor DNA could help in the early detection of systemic metastases.

  View details for DOI 10.18632/oncotarget.23174

  View details for PubMedID 29371980

  View details for PubMedCentralID PMC5768397

• Diffuse midline gliomas with subclonal H3F3A K27M mutation and mosaic H3.3 K27M mutant protein expression. Acta neuropathologica Lopez, G. Y., Oberheim Bush, N. A., Phillips, J. J., Bouffard, J. P., Moshel, Y. A., Jaeckle, K., Kleinschmidt-DeMasters, B. K., Rosenblum, M. K., Perry, A., Solomon, D. A. 2017; 134 (6): 961-963

  View details for DOI 10.1007/s00401-017-1780-0

  View details for PubMedID 29063183

  View details for PubMedCentralID PMC6078201

• Complete durable response of a pediatric anaplastic oligodendroglioma to temozolomide alone: Case report and review of literature. Pediatric blood & cancer Sorge, C., Li, R., Singh, S., Reddy, A. T., Solomon, D. A., Perry, A., Friedman, G. K. 2017; 64 (12)

  Abstract

  Anaplastic oligodendroglioma (AO) is rare in children. Treatment typically consists of varying combinations of surgery, chemotherapy, and radiotherapy. We present a pediatric case of frontal lobe AO with periventricular subcallosal extension and local leptomeningeal involvement. The isocitrate dehydrogenase (IDH) wild-type tumor was MGMT methylated and contained an ATRX mutation, BRAF alteration, and 1p/19q co-deletion; a combination of alterations mostly encountered in pediatric oligodendrogliomas. The patient underwent a near total resection and had a complete, durable response to temozolomide alone, suggesting that conservative management without radiation may be appropriate in some cases. We review the literature of this uncommon subtype of glioma in children.

  View details for DOI 10.1002/pbc.26708

  View details for PubMedID 28696020

  View details for PubMedCentralID PMC8408833

• Angiocentric glioma with MYB-QKI fusion located in the brainstem, rather than cerebral cortex. Acta neuropathologica Chan, E., Bollen, A. W., Sirohi, D., Van Ziffle, J., Grenert, J. P., Kline, C. N., Tihan, T., Perry, A., Gupta, N., Solomon, D. A. 2017; 134 (4): 671-673

  View details for DOI 10.1007/s00401-017-1759-x

  View details for PubMedID 28776091

  View details for PubMedCentralID PMC5693679

• Familial melanoma-astrocytoma syndrome: synchronous diffuse astrocytoma and pleomorphic xanthoastrocytoma in a patient with germline CDKN2A/B deletion and a significant family history. Clinical neuropathology Chan, A. K., Han, S. J., Choy, W., Beleford, D., Aghi, M. K., Berger, M. S., Shieh, J. T., Bollen, A. W., Perry, A., Phillips, J. J., Butowski, N., Solomon, D. A. 2017; 36 (5): 213-221

  Abstract

  Familial melanoma-astrocytoma syndrome is a tumor predisposition syndrome caused by inactivating germline alteration of the CDKN2A tumor suppressor gene on chromosome 9p21. While some families with germline CDKN2A mutations are prone to development of just melanomas, other families develop both melanomas, astrocytomas, and occasionally other nervous-system neoplasms including peripheral nerve sheath tumors and meningiomas. The histologic spectrum of the astrocytomas that arise as part of this syndrome is not well described, nor are the additional genetic alterations that drive these astrocytomas apart from the germline CDKN2A inactivation. Herein, we report the case of a young man with synchronous development of a pleomorphic xanthoastrocytoma, diffuse astrocytoma, and paraspinal mass radiographically consistent with a peripheral nerve sheath tumor. His paternal family history is significant for melanoma, glioblastoma, and oral squamous cell carcinoma. Genomic profiling revealed that he harbors a heterozygous deletion in the germline of chromosome 9p21.3 encompassing the CDKN2A and CDKN2B tumor suppressor genes. Both the pleomorphic xanthoastrocytoma and diffuse astrocytoma were found to have homozygous deletion of CDKN2A/B due to somatic loss of the other copy of chromosome 9p containing the remaining intact alleles. Additional somatic alterations included BRAF p.V600E mutation in the pleomorphic xanthoastrocytoma and PTPN11, ATRX, and NF1 mutations in the diffuse astrocytoma. The presence of germline CDKN2A/B inactivation together with the presence of multiple anatomically, histologically, and genetically distinct astrocytic neoplasms, both with accompanying somatic loss of heterozygosity for the CDKN2A/B deletion, led to a diagnosis of familial melanoma-astrocytoma syndrome. This remarkable case illustrates the histologic and genetic diversity that astrocytomas arising as part of this rare glioma predisposition syndrome can demonstrate..

  View details for DOI 10.5414/NP301022

  View details for PubMedID 28699883

  View details for PubMedCentralID PMC5628627

• Case-based review: pediatric medulloblastoma. Neuro-oncology practice Kline, C. N., Packer, R. J., Hwang, E. I., Raleigh, D. R., Braunstein, S., Raffel, C., Bandopadhayay, P., Solomon, D. A., Aboian, M., Cha, S., Mueller, S. 2017; 4 (3): 138-150

  Abstract

  Medulloblastoma is the most common malignant brain tumor affecting children. These tumors are high grade with propensity to metastasize within the central nervous system and, less frequently, outside the neuraxis. Recent advancements in molecular subgrouping of medulloblastoma refine diagnosis and improve counseling in regards to overall prognosis. Both are predicated on the molecular drivers of each subgroup-WNT-activated, SHH-activated, group 3, and group 4. The traditional therapeutic mainstay for medulloblastoma includes a multimodal approach with surgery, radiation, and multiagent chemotherapy. As we discover more about the molecular basis of medulloblastoma, efforts to adjust treatment approaches based on molecular risk stratification are under active investigation. Certainly, the known neurological, developmental, endocrine, and psychosocial injury related to medulloblastoma and its associated therapies motivate ongoing research towards improving treatment for this life-threatening tumor while at the same time minimizing long-term side effects.

  View details for DOI 10.1093/nop/npx011

  View details for PubMedID 29692919

  View details for PubMedCentralID PMC5909805

• Characterization of gliomas: from morphology to molecules. Virchows Archiv : an international journal of pathology Ferris, S. P., Hofmann, J. W., Solomon, D. A., Perry, A. 2017; 471 (2): 257-269

  Abstract

  This article reviews the histologic and molecular characterization of gliomas, including the new "integrated diagnoses" of the World Health Organization Classification, 2016 edition. The entities reviewed within include diffuse gliomas (astrocytoma, oligodendroglioma, glioblastoma), as well as circumscribed and low-grade gliomas (angiocentric glioma, pilocytic astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma, pilomyxoid astrocytoma, ependymoma, myxopapillary ependymoma, and subependymoma). Diagnostic, prognostic, and predictive biomarkers are discussed for each entity. We review how molecular testing for IDH1 and ATRX and detection of chromosome 1p/19q codeletion can be used to categorize glioblastomas as IDH-wildtype or IDH-mutant, and lower grade diffuse gliomas into three molecular groups that correlate better with patient outcomes than histologic subtyping. Pediatric diffuse gliomas are highlighted, including diffuse midline glioma, H3 K27M-mutant, and inherited germline mutations that predispose to pediatric gliomas. The utility of genomic profiling of certain gliomas is discussed, including identifying candidates for experimental therapies. This review is meant to be a concise summary of glioma characterization for the practicing pathologist.

  View details for DOI 10.1007/s00428-017-2181-4

  View details for PubMedID 28674742

• Uveal Ganglioneuroma due to Germline PTEN Mutation (Cowden Syndrome) Presenting as Unilateral Infantile Glaucoma. Ocular oncology and pathology DeParis, S. W., Bloomer, M., Han, Y., Vagefi, M. R., Shieh, J. T., Solomon, D. A., Grenert, J., de Alba Campomanes, A. G. 2017; 3 (2): 122-128

  Abstract

  Uveal ganglioneuroma is a rare tumor that usually occurs in association with neurofibromatosis type 1. Here, we present a rare case of a uveal ganglioneuroma leading to a diagnosis of the tumor predisposition condition Cowden syndrome.A 5-year-old girl with unilateral refractory glaucoma secondary to diffuse iris and choroidal thickening developed a blind, painful eye. Enucleation was performed, and histopathology revealed infiltration of the entire uveal tract by neoplastic spindle cells containing admixed ganglion cells diagnostic of uveal ganglioneuroma. Targeted next-generation sequencing of 510 cancer-associated genes was performed on tumor tissue and peripheral blood.A germline nonsense mutation in the PTEN gene was found, accompanied by loss of heterozygosity in the tumor. A diagnosis of Cowden syndrome was made, for which the family sought genetic counseling and initiated the recommended cancer screening.A novel association is found between uveal ganglioneuroma and Cowden syndrome, emphasizing the value of genetic tissue testing in managing patients with rare ocular tumors.

  View details for DOI 10.1159/000450552

  View details for PubMedID 28868283

  View details for PubMedCentralID PMC5566766

• Intraneural glomus tumor of "uncertain malignant potential" and with BRAF mutation in the median nerve - an unusual case. Clinical neuropathology Dahlin, L. B., Scherman, P., Besjakov, J., Lindberg, E., Solomon, D. A., Horvai, A. E., Perry, A. 2017; 36 (4): 164-170

  Abstract

  A glomus tumor of uncertain malignant potential is defined as a glomus tumor with some, but not all, criteria for malignancy and without a known metastasis. Here, we present a rare example presenting in the median nerve in a 40-year-old woman with a long history of severely impaired left median nerve function. A large panel of immunohistochemical stains excluded other diagnoses, and the designation of a "uncertain malignant potential" was based on the high proliferative activity, the tumor size and location, and the lack of WHO malignancy criteria such as marked nuclear atypia, necrosis, or atypical mitoses. A BRAF mutation was found in the tumor. Although extremely rare, both benign and malignant glomus tumors may present in large peripheral nerves and should therefore be considered in the differential diagnosis..

  View details for DOI 10.5414/NP300989

  View details for PubMedID 28438258

• Genomic profiling of breast secretory carcinomas reveals distinct genetics from other breast cancers and similarity to mammary analog secretory carcinomas. Modern pathology Krings, G., Joseph, N. M., Bean, G. R., Solomon, D., Onodera, C., Talevich, E., Yeh, I., Grenert, J. P., Hosfield, E., Crawford, E. D., Jordan, R. C., van Zante, A., Zaloudek, C., Shin, S. J., Chen, Y. 2017

  Abstract

  Secretory carcinomas of the breast are rare tumors with distinct histologic features, recurrent t(12;15)(p13;q25) translocation resulting in ETV6-NTRK3 gene fusion and indolent clinical behavior. Mammary analog secretory carcinomas arising in other sites are histopathologically similar to the breast tumors and also harbor ETV6-NTRK3 fusions. Breast secretory carcinomas are often triple (estrogen and progesterone receptor, HER2) negative with a basal-like immunophenotype. However, genomic studies are lacking, and whether these tumors share genetic features with other basal and/or triple negative breast cancers is unknown. Aside from shared ETV6-NTRK3 fusions, the genetic relatedness of secretory carcinomas arising in different sites is also uncertain. We immunoprofiled and sequenced 510 cancer-related genes in nine breast secretory carcinomas and six salivary gland mammary analog secretory carcinomas. Immunoprofiles of breast and salivary gland secretory carcinomas were similar. All the tumors showed strong diffuse MUC4 expression (n=15), and SOX10 was positive in all nine breast and in five out of six salivary gland tumors. All breast secretory carcinomas were triple negative or weakly ER-positive, and all tumors at both the sites expressed CK5/6 and/or EGFR, consistent with a basal-like phenotype. Sequencing revealed classic ETV6-NTRK3 fusion genes in all cases, including in carcinoma in situ of one breast tumor. Translocations were reciprocal and balanced in six out of nine breast and three out of six salivary gland tumors and were complex in three others. In contrast to most breast basal carcinomas, the mutational burden of secretory carcinomas was very low, and no additional pathogenic aberrations were identified in genes typically mutated in breast cancer. Five (56%) breast and two (33%) salivary gland tumors had simple genomes without copy number changes; the remainder had very few changes, averaging 1.3 per tumor. The ETV6-NTRK3 derivative chromosome was duplicated in one breast and one salivary gland tumor, and was the only copy number change in the latter. The findings highlight breast secretory carcinoma as a subtype more closely related to mammary analog secretory carcinoma than to basal/triple negative breast cancers of no special type. Lack of pathogenic mutations in common cancer-related genes suggests that ETV6-NTRK3 alone may suffice to drive these tumors and likely helps explain their indolent behavior.

  View details for DOI 10.1038/modpathol.2017.32

  View details for PubMedID 28548128

• Diffuse non-midline glioma with H3F3A K27M mutation: a prognostic and treatment dilemma. Acta neuropathologica communications López, G., Oberheim Bush, N. A., Berger, M. S., Perry, A., Solomon, D. A. 2017; 5 (1): 38

  View details for DOI 10.1186/s40478-017-0440-x

  View details for PubMedID 28506301

  View details for PubMedCentralID PMC5433088

• Chordoid glioma of the third ventricle: report of a rapidly progressive case. Journal of neuro-oncology Erwood, A. A., Velazquez-Vega, J. E., Neill, S., Solomon, D. A., Butowski, N., Nowlan, A., Dunbar, E., Brat, D. J. 2017; 132 (3): 487-495

  Abstract

  Chordoid gliomas are slowly growing third ventricular tumors that can be challenging to manage clinically. Rapid progression causing death has not been previously reported for this tumor type. We present and discuss a case of chordoid glioma that arose in a 46-year-old female who presented with progressive fatigue, headache, and altered mental status, attributable to severe hydrocephalus caused by a third ventricular mass. She underwent urgent subtotal resection and ventriculo-peritoneal shunt placements. Post-operative MRI noted residual tumor in the anterior resection cavity. An MRI performed 9 weeks later showed substantial progression, with marked tumor enlargement and compression of adjacent hypothalamic structures and the optic chiasm. Despite a course of radiation therapy, the tumor continued to enlarge, and the patient died from tumor progression 7 months after initial presentation. Post-mortem exam demonstrated a mass that expanded the third ventricle and compressed adjacent hypothalamic, thalamic and suprasellar structures. Histologic and immunohistochemical studies confirmed a chordoid glioma and revealed multifocal coagulative necrosis and intravascular thrombosis, which are unusual in this tumor type. Cytogenomic microarray testing revealed numerous DNA copy number abnormalities, many of which had not previously been reported in this tumor. The pathologic and cytogenetic changes may correlate with the aggressive behavior of this chordoid glioma and can be pursued by future investigation of additional cases.

  View details for DOI 10.1007/s11060-017-2399-7

  View details for PubMedID 28315998

• Genetic confirmation that ependymoma can arise as part of multiple endocrine neoplasia type 1 (MEN1) syndrome. Acta neuropathologica Cuevas-Ocampo, A. K., Bollen, A. W., Goode, B., Pajtler, K. W., Chavez, L., Sharma, T., Dai, S. C., McDermott, M., Perry, A., Korshunov, A., Solomon, D. A. 2017; 133 (4): 661-663

  View details for DOI 10.1007/s00401-017-1689-7

  View details for PubMedID 28238068

  View details for PubMedCentralID PMC5391795

• The role of histone modifications and telomere alterations in the pathogenesis of diffuse gliomas in adults and children. Journal of neuro-oncology Lee, J., Solomon, D. A., Tihan, T. 2017; 132 (1): 1-11

  Abstract

  Genetic profiling is an increasingly useful tool for sub-classification of gliomas in adults and children. Specific gene mutations, structural rearrangements, DNA methylation patterns, and gene expression profiles are now recognized to define molecular subgroups of gliomas that arise in distinct anatomic locations and patient age groups, and also provide a better prediction of clinical outcomes for glioma patients compared to histologic assessment alone. Understanding the role of these distinctive genetic alterations in gliomagenesis is also important for the development of potential targeted therapeutic interventions. Mutations including K27M and G34R/V that affect critical amino acids within the N-terminal tail of the histone H3 variants, H3.3 and H3.1 (encoded by H3F3A and HIST1H3B genes), are prime examples of mutations in diffuse gliomas with characteristic clinical associations that can help diagnostic classification and guide effective patient management. These histone H3 mutations frequently co-occur with inactivating mutations in ATRX in association with alternative lengthening of telomeres. Telomere length can also be maintained through upregulation of telomerase reverse transcriptase (TERT) expression driven by mutation within the TERT gene promoter region, an alteration most commonly found in oligodendrogliomas and primary glioblastomas arising in adults. Interestingly, the genetic alterations perturbing histone and telomere function in pediatric gliomas tend to be different from those present in adult tumors. We present a review of these mutations affecting the histone code and telomere length, highlighting their importance in prognosis and as targets for novel therapeutics in the treatment of diffuse gliomas.

  View details for DOI 10.1007/s11060-016-2349-9

  View details for PubMedID 28064387

  View details for PubMedCentralID PMC5354997

• Genomic profiling of malignant peritoneal mesothelioma reveals recurrent alterations in epigenetic regulatory genes BAP1, SETD2, and DDX3X. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc Joseph, N. M., Chen, Y. Y., Nasr, A., Yeh, I., Talevich, E., Onodera, C., Bastian, B. C., Rabban, J. T., Garg, K., Zaloudek, C., Solomon, D. A. 2017; 30 (2): 246-254

  Abstract

  Malignant mesothelioma is a rare cancer that arises from the mesothelial cells that line the pleural cavity and less commonly from the peritoneal lining of the abdomen and pelvis. Most pleural mesotheliomas arise in patients with a history of asbestos exposure, whereas the association of peritoneal mesotheliomas with exposure to asbestos and other potential carcinogens is less clear, suggesting that the genetic alterations that drive malignant peritoneal mesothelioma may be unique from those in pleural mesothelioma. Treatment options for all malignant mesotheliomas are currently limited, with no known targeted therapies available. To better understand the molecular pathogenesis of malignant peritoneal mesothelioma, we sequenced 510 cancer-related genes in 13 patients with malignant mesothelioma arising in the peritoneal cavity. The most frequent genetic alteration was biallelic inactivation of the BAP1 gene, which occurred in 9/13 cases, with an additional two cases demonstrating monoallelic loss of BAP1. All 11 of these cases demonstrated loss of BAP1 nuclear staining by immunohistochemistry, whereas two tumors without BAP1 alteration and all 42 cases of histologic mimics in peritoneum (8 multilocular peritoneal inclusion cyst, 6 well-differentiated papillary mesothelioma of the peritoneum, 16 adenomatoid tumor, and 12 low-grade serous carcinoma of the ovary) demonstrated intact BAP1 nuclear staining. Additional recurrently mutated genes in this cohort of malignant peritoneal mesotheliomas included NF2 (3/13), SETD2 (2/13), and DDX3X (2/13). While these genes are known to be recurrently mutated in pleural mesotheliomas, the frequencies are distinct in peritoneal mesotheliomas, with nearly 85% of peritoneal tumors harboring BAP1 alterations versus only 20-30% of pleural tumors. Together, these findings demonstrate the importance of epigenetic modifiers including BAP1, SETD2, and DDX3X in mesothelial tumorigenesis and suggest opportunities for targeted therapies.

  View details for DOI 10.1038/modpathol.2016.188

  View details for PubMedID 27813512

  View details for PubMedCentralID PMC5288276

• Histopathologic review of pineal parenchymal tumors identifies novel morphologic subtypes and prognostic factors for outcome. Neuro-oncology Raleigh, D. R., Solomon, D. A., Lloyd, S. A., Lazar, A., Garcia, M. A., Sneed, P. K., Clarke, J. L., McDermott, M. W., Berger, M. S., Tihan, T., Haas-Kogan, D. A. 2017; 19 (1): 78-88

  Abstract

  Pineal parenchymal tumors (PPTs) are rare neoplasms of the central nervous system, and data concerning clinical outcomes are limited. The purpose of this study was to define the clinical behavior of PPT according to current histopathologic criteria and identify prognostic factors to guide therapeutic decisions.Seventy-five patients treated for PPT at a single institution between 1992 and 2015 were retrospectively identified. Forty-five resection specimens were available and re-reviewed. Freedom from progression (FFP) and overall survival (OS) were estimated using the Kaplan-Meier method and compared using log-rank tests.Median follow-up was 4.1 years. All patients initially underwent surgery; 78% of patients with PPT of intermediate differentiation (PPTID) and all patients with pineoblastoma received adjuvant therapy. Pathologic re-review refined classification in 27% of cases, with the majority of these being adult patients with pineal tumors originally classified as pineoblastomas that more accurately resembled PPTID based on the 2007 WHO classification.Our histologic review also identified that PPTIDs can be classified into small-cell and large-cell morphologic subtypes, which have distinct clinical outcomes. Tumor grade, extent of resection, and neuraxis spread were prognostic for FFP. PPTID subtype, extent of resection, and neuraxis spread were prognostic for OS. Genetic analysis of a pineoblastoma case identified somatic mutations of DICER1, ARID1A, and KDM5C genes.PPTIDs can be classified into 1 of 2 novel morphologic subtypes that are associated with distinct clinical outcomes. Tumor grade, neuraxis spread, and extent of resection also influence outcome for patients with PPT.

  View details for DOI 10.1093/neuonc/now105

  View details for PubMedID 27282397

  View details for PubMedCentralID PMC5193017

• Pancreatic involvement by mesenchymal chondrosarcoma harboring the HEY1-NCOA2 gene fusion. Human pathology Cohen, J. N., Solomon, D. A., Horvai, A. E., Kakar, S. 2016; 58: 35-40

  Abstract

  Mesenchymal chondrosarcoma (MC) is an aggressive small, round, blue cell tumor with chondrogenic differentiation that typically arises in bony sites. Approximately, a third of these tumors develop in extraskeletal sites such as the meninges, and somatic soft tissue. The MCs are well-circumscribed, lobulated masses, with focal calcification. Histologically, 2 distinct populations of neoplastic cells characterize MC: sheets of primitive small, round, blue cells surrounding islands of well-developed hyaline cartilage with mature chondrocytes in lacunae. Involvement of the gastrointestinal tract and pancreas by primary or metastatic MC is a relatively rare occurrence. We identified 8 patients with MC in our departmental archives from 1990 to 2015, two of which had pancreatic involvement. The patients were young women who developed masses in the distal pancreas. Molecular testing demonstrated that both tumors harbored the recently described HEY1-NCOA2 gene fusion. These cases illustrate that pancreatic involvement can occur in MC, and the demonstration of HEY1-NCOA2 fusion can be helpful to confirm the diagnosis.

  View details for DOI 10.1016/j.humpath.2016.07.026

  View details for PubMedID 27544802

• Correlation of exon 3 β-catenin mutations with glutamine synthetase staining patterns in hepatocellular adenoma and hepatocellular carcinoma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc Hale, G., Liu, X., Hu, J., Xu, Z., Che, L., Solomon, D., Tsokos, C., Shafizadeh, N., Chen, X., Gill, R., Kakar, S. 2016; 29 (11): 1370-1380

  Abstract

  The current clinical practice is based on the assumption of strong correlation between diffuse glutamine synthetase expression and β-catenin activation in hepatocellular adenoma and hepatocellular carcinoma. This high correlation is based on limited data and may represent an oversimplification as glutamine synthetase staining patterns show wide variability in clinical practice. Standardized criteria for interpreting diverse glutamine synthetase patterns, and the association between each pattern and β-catenin mutations is not clearly established. This study examines the correlation between glutamine synthetase staining patterns and β-catenin mutations in 15 typical hepatocellular adenomas, 5 atypical hepatocellular neoplasms and 60 hepatocellular carcinomas. Glutamine synthetase staining was classified into one of the three patterns: (a) diffuse homogeneous: moderate-to-strong cytoplasmic staining in >90% of lesional cells, without a map-like pattern, (b) diffuse heterogeneous: moderate-to-strong staining in 50-90% of lesional cells, without a map-like pattern, and (c) patchy: moderate-to-strong staining in <50% of lesional cells (often perivascular), or weak staining irrespective of the extent, and all other staining patterns (including negative cases). Sanger sequencing of CTNNB1 exon 3 was performed in all cases. Of hepatocellular tumors with diffuse glutamine synthetase staining (homogeneous or heterogeneous), an exon 3 β-catenin mutation was detected in 33% (2/6) of typical hepatocellular adenoma, 75% (3/4) of atypical hepatocellular neoplasm and 17% (8/47) of hepatocellular carcinomas. An exon 3 mutation was also observed in 15% (2/13) of hepatocellular carcinomas with patchy glutamine synthetase staining. The results show a modest correlation between diffuse glutamine synthetase immunostaining and exon 3 β-catenin mutations in hepatocellular adenoma and hepatocellular carcinoma with discrepancy rates >50% in both hepatocellular adenoma and hepatocellular carcinoma. The interpretation of β-catenin activation based on glutamine synthetase staining should be performed with caution, and the undetermined significance of various glutamine synthetase patterns should be highlighted in pathology reports.

  View details for DOI 10.1038/modpathol.2016.122

  View details for PubMedID 27469330

  View details for PubMedCentralID PMC5149418

• Activating NRF1-BRAF and ATG7-RAF1 fusions in anaplastic pleomorphic xanthoastrocytoma without BRAF p.V600E mutation. Acta neuropathologica Phillips, J. J., Gong, H., Chen, K., Joseph, N. M., van Ziffle, J., Jin, L. W., Bastian, B. C., Bollen, A. W., Perry, A., Nicolaides, T., Solomon, D. A., Shieh, J. T. 2016; 132 (5): 757-760

  View details for DOI 10.1007/s00401-016-1616-3

  View details for PubMedID 27624885

  View details for PubMedCentralID PMC5074852

• Diffuse Midline Gliomas with Histone H3-K27M Mutation: A Series of 47 Cases Assessing the Spectrum of Morphologic Variation and Associated Genetic Alterations. Brain pathology (Zurich, Switzerland) Solomon, D. A., Wood, M. D., Tihan, T., Bollen, A. W., Gupta, N., Phillips, J. J., Perry, A. 2016; 26 (5): 569-80

  Abstract

  Somatic mutations of the H3F3A and HIST1H3B genes encoding the histone H3 variants, H3.3 and H3.1, were recently identified in high-grade gliomas arising in the thalamus, pons and spinal cord of children and young adults. However, the complete range of patients and locations in which these tumors arise, as well as the morphologic spectrum and associated genetic alterations remain undefined. Here, we describe a series of 47 diffuse midline gliomas with histone H3-K27M mutation. The 25 male and 22 female patients ranged in age from 2 to 65 years (median = 14). Tumors were centered not only in the pons, thalamus, and spinal cord, but also in the third ventricle, hypothalamus, pineal region and cerebellum. Patients with pontine tumors were younger (median = 7 years) than those with thalamic (median = 24 years) or spinal (median = 25 years) tumors. A wide morphologic spectrum was encountered including gliomas with giant cells, epithelioid and rhabdoid cells, primitive neuroectodermal tumor (PNET)-like foci, neuropil-like islands, pilomyxoid features, ependymal-like areas, sarcomatous transformation, ganglionic differentiation and pleomorphic xanthoastrocytoma (PXA)-like areas. In this series, histone H3-K27M mutation was mutually exclusive with IDH1 mutation and EGFR amplification, rarely co-occurred with BRAF-V600E mutation, and was commonly associated with p53 overexpression, ATRX loss (except in pontine gliomas), and monosomy 10.

  View details for DOI 10.1111/bpa.12336

  View details for PubMedID 26517431

  View details for PubMedCentralID PMC6055926

• IDH1 mutation can be present in diffuse astrocytomas and giant cell glioblastomas of young children under 10 years of age. Acta neuropathologica Ferris, S. P., Goode, B., Joseph, N. M., Kline, C. N., Samuel, D., Gupta, N., Bollen, A., Perry, A., Mueller, S., Solomon, D. A. 2016; 132 (1): 153-5

  View details for DOI 10.1007/s00401-016-1579-4

  View details for PubMedID 27161253

  View details for PubMedCentralID PMC4915961

• Exploiting molecular biology for diagnosis and targeted management of pediatric low-grade gliomas. Future oncology (London, England) Garcia, M. A., Solomon, D. A., Haas-Kogan, D. A. 2016; 12 (12): 1493-506

  Abstract

  The majority of brain tumors arising in children are low-grade gliomas. Although historically categorized together as pediatric low-grade gliomas (PLGGs), there is significant histologic and genetic diversity within this group. In general, prognosis for PLGGs is excellent, and limitation of sequelae from tumor and treatment is paramount. Advances in high-throughput genetic sequencing and gene expression profiling are fundamentally changing the way PLGGs are classified and managed. Here, we review the histologic subtypes and highlight how recent advances in elucidating the molecular pathogenesis of these tumors have refined diagnosis and prognostication. Additionally, we discuss how characterizing specific genetic alterations has paved the way for the rational use of targeted therapies that are currently in various phase clinical trials.

  View details for DOI 10.2217/fon-2016-0039

  View details for PubMedID 27072750

  View details for PubMedCentralID PMC4915741

• Inactivating MUTYH germline mutations in pediatric patients with high-grade midline gliomas. Neuro-oncology Kline, C. N., Joseph, N. M., Grenert, J. P., van Ziffle, J., Yeh, I., Bastian, B. C., Mueller, S., Solomon, D. A. 2016; 18 (5): 752-3

  View details for DOI 10.1093/neuonc/now013

  View details for PubMedID 26902849

  View details for PubMedCentralID PMC4827050

• Morphology and Immunohistochemistry for 2SC and FH Aid in Detection of Fumarate Hydratase Gene Aberrations in Uterine Leiomyomas From Young Patients. The American journal of surgical pathology Joseph, N. M., Solomon, D. A., Frizzell, N., Rabban, J. T., Zaloudek, C., Garg, K. 2015; 39 (11): 1529-39

  Abstract

  Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome is an autosomal dominant syndrome that results from mutations in the fumarate hydratase (FH) gene. Patients with HLRCC are at risk for smooth muscle tumors of the uterus and skin as well as renal tumors. The renal cell carcinomas associated with HLRCC are usually high stage at presentation, aggressive, and have poor clinical outcomes. Therefore these patients and family members would benefit from early identification and appropriate surveillance. In small studies, HLRCC-associated uterine leiomyomas have been noted to display characteristic morphologic features including eosinophilic cytoplasmic inclusions, prominent eosinophilic nucleoli, and perinucleolar halos. Limited data suggest that positive staining for 2-succinocysteine (2SC) and loss of staining for FH by immunohistochemistry (IHC) can help with identification of HLRCC. The aim of this study was to evaluate the ability of morphology and IHC for FH and 2SC to help identify HLRCC in young patients with uterine smooth muscle tumors. We identified 194 evaluable uterine leiomyomas from women less than 40 years of age. We found FH gene aberrations by mutation analysis in 5 cases, a 2.6% incidence. Of these 5 cases, 4 displayed the characteristic morphologic features outlined above, whereas 1 did not. All 5 tumors with FH gene abnormalities showed positive staining for 2SC, whereas no FH gene aberrations were found in the 2SC-negative cases. Loss of FH staining was seen in 2 of the 5 cases, 1 with frameshift mutation and the other with homozygous deletion, whereas the remaining 3 cases with missense FH gene mutations were FH positive. Our study shows that morphologic features can be helpful for detection of HLRCC in uterine leiomyomas, although they may not be present in every case. IHC for 2SC and FH can be helpful: presence of positive staining for 2SC is sensitive and specific for detection of FH gene aberrations, whereas loss of staining for FH is specific but not sufficiently sensitive, as cases with missense mutations in the FH gene can show retained staining.

  View details for DOI 10.1097/PAS.0000000000000520

  View details for PubMedID 26457356

• Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma NATURE MEDICINE Hashizume, R., Andor, N., Ihara, Y., Lerner, R., Gan, H., Chen, X., Fang, D., Huang, X., Tom, M. W., Ngo, V., Solomon, D., Mueller, S., Paris, P. L., Zhang, Z., Petritsch, C., Gupta, N., Waldman, T. A., James, C. D. 2014; 20 (12): 1394-1396

  Abstract

  Pediatric brainstem gliomas often harbor oncogenic K27M mutation of histone H3.3. Here we show that GSKJ4 pharmacologic inhibition of K27 demethylase JMJD3 increases cellular H3K27 methylation in K27M tumor cells and demonstrate potent antitumor activity both in vitro against K27M cells and in vivo against K27M xenografts. Our results demonstrate that increasing H3K27 methylation by inhibiting K27 demethylase is a valid therapeutic strategy for treating K27M-expressing brainstem glioma.

  View details for DOI 10.1038/nm.3716

  View details for Web of Science ID 000345817900013

  View details for PubMedID 25401693

  View details for PubMedCentralID PMC4257862

• Clinicopathologic features of a second patient with Ewing-like sarcoma harboring CIC-FOXO4 gene fusion. The American journal of surgical pathology Solomon, D. A., Brohl, A. S., Khan, J., Miettinen, M. 2014; 38 (12): 1724-5

  View details for DOI 10.1097/PAS.0000000000000335

  View details for PubMedID 25321332

  View details for PubMedCentralID PMC4229425

• Mutational and functional analysis of the tumor-suppressor PTPRD in human melanoma. Human mutation Walia, V., Prickett, T. D., Kim, J. S., Gartner, J. J., Lin, J. C., Zhou, M., Rosenberg, S. A., Elble, R. C., Solomon, D. A., Waldman, T., Samuels, Y. 2014; 35 (11): 1301-10

  Abstract

  Protein tyrosine phosphatases (PTPs) tightly regulate tyrosine phosphorylation essential for cell growth, adhesion, migration, and survival. We performed a mutational analysis of the PTP gene family in cutaneous metastatic melanoma and identified 23 phosphatase genes harboring somatic mutations. Among these, receptor-type tyrosine-protein phosphatase delta (PTPRD) was one of the most highly mutated genes, harboring 17 somatic mutations in 79 samples, a prevalence of 21.5%. Functional evaluation of six PTPRD mutations revealed enhanced anchorage-dependent and anchorage-independent growth. Interestingly, melanoma cells expressing mutant PTPRD were significantly more migratory than cells expressing wild-type PTPRD or vector alone, indicating a novel gain-of-function associated with mutant PTPRD. To understand the molecular mechanisms of PTPRD mutations, we searched for its binding partners by converting the active PTPRD enzyme into a "substrate trap" form. Using mass spectrometry and coimmunoprecipitation, we report desmoplakin, a desmosomal protein that is implicated in cell-cell adhesion, as a novel PTPRD substrate. Further analysis showed reduced phosphatase activity of mutant PTPRD against desmoplakin. Our findings identify an essential signaling cascade that is disrupted in melanoma. Moreover, because PTPRD is also mutated in glioblastomas and adenocarcinoma of the colon and lung, our data might be applicable to a large number of human cancers.

  View details for DOI 10.1002/humu.22630

  View details for PubMedID 25113440

  View details for PubMedCentralID PMC4394620

• Aneurysm of the posterior meningeal artery embedded within a dorsal exophytic medullary hemangioblastoma: surgical management and review of literature. Journal of cerebrovascular and endovascular neurosurgery Raygor, K. P., Rowland, N. C., Cooke, D. L., Solomon, D. A., Huang, M. C. 2014; 16 (3): 293-8

  Abstract

  Hemangioblastomas are World Health Organization (WHO) Grade I neoplasms of the hindbrain and spinal cord, whose management can be complicated by preoperative hemorrhage. We report on a case of a young female in extremis with posterior fossa hemorrhage following rupture of a fusiform posterior meningeal artery aneurysm embedded within a medullary hemangioblastoma. We discuss management options, including operative staging and embolization, and review similar cases of hemangioblastoma associated with aneurysm.

  View details for DOI 10.7461/jcen.2014.16.3.293

  View details for PubMedID 25340034

  View details for PubMedCentralID PMC4205258

• Cohesin gene mutations in tumorigenesis: from discovery to clinical significance. BMB reports Solomon, D. A., Kim, J. S., Waldman, T. 2014; 47 (6): 299-310

  Abstract

  Cohesin is a multi-protein complex composed of four core subunits (SMC1A, SMC3, RAD21, and either STAG1 or STAG2) that is responsible for the cohesion of sister chromatids following DNA replication until its cleavage during mitosis thereby enabling faithful segregation of sister chromatids into two daughter cells. Recent cancer genomics analyses have discovered a high frequency of somatic mutations in the genes encoding the core cohesin subunits as well as cohesin regulatory factors (e.g. NIPBL, PDS5B, ESPL1) in a select subset of human tumors including glioblastoma, Ewing sarcoma, urothelial carcinoma, acute myeloid leukemia, and acute megakaryoblastic leukemia. Herein we review these studies including discussion of the functional significance of cohesin inactivation in tumorigenesis and potential therapeutic mechanisms to selectively target cancers harboring cohesin mutations.

  View details for DOI 10.5483/bmbrep.2014.47.6.092

  View details for PubMedID 24856830

  View details for PubMedCentralID PMC4163871

• Glioblastoma cells containing mutations in the cohesin component STAG2 are sensitive to PARP inhibition. Molecular cancer therapeutics Bailey, M. L., O'Neil, N. J., van Pel, D. M., Solomon, D. A., Waldman, T., Hieter, P. 2014; 13 (3): 724-32

  Abstract

  Recent data have identified STAG2, a core subunit of the multifunctional cohesin complex, as a highly recurrently mutated gene in several types of cancer. We sought to identify a therapeutic strategy to selectively target cancer cells harboring inactivating mutations of STAG2 using two independent pairs of isogenic glioblastoma cell lines containing either an endogenous mutant STAG2 allele or a wild-type STAG2 allele restored by homologous recombination. We find that mutations in STAG2 are associated with significantly increased sensitivity to inhibitors of the DNA repair enzyme PARP. STAG2-mutated, PARP-inhibited cells accumulated in G2 phase and had a higher percentage of micronuclei, fragmented nuclei, and chromatin bridges compared with wild-type STAG2 cells. We also observed more 53BP1 foci in STAG2-mutated glioblastoma cells, suggesting that these cells have defects in DNA repair. Furthermore, cells with mutations in STAG2 were more sensitive than cells with wild-type STAG2 when PARP inhibitors were used in combination with DNA-damaging agents. These data suggest that PARP is a potential target for tumors harboring inactivating mutations in STAG2, and strongly recommend that STAG2 status be determined and correlated with therapeutic response to PARP inhibitors, both prospectively and retrospectively, in clinical trials.

  View details for DOI 10.1158/1535-7163.MCT-13-0749

  View details for PubMedID 24356817

  View details for PubMedCentralID PMC4130349

• Hemosiderotic fibrolipomatous tumor, not an entirely benign entity. The American journal of surgical pathology Solomon, D. A., Antonescu, C. R., Link, T. M., O'Donnell, R. J., Folpe, A. L., Horvai, A. E. 2013; 37 (10): 1627-30

  View details for DOI 10.1097/PAS.0b013e31829ff078

  View details for PubMedID 24025526

• Targeted therapy for BRAFV600E malignant astrocytoma. Clinical cancer research : an official journal of the American Association for Cancer Research Nicolaides, T. P., Li, H., Solomon, D. A., Hariono, S., Hashizume, R., Barkovich, K., Baker, S. J., Paugh, B. S., Jones, C., Forshew, T., Hindley, G. F., Hodgson, J. G., Kim, J. S., Rowitch, D. H., Weiss, W. A., Waldman, T. A., James, C. D. 2011; 17 (24): 7595-604

  Abstract

  Malignant astrocytomas (MA) are aggressive central nervous system tumors with poor prognosis. Activating mutation of BRAF (BRAF(V600E)) has been reported in a subset of these tumors, especially in children. We have investigated the incidence of BRAF(V600E) in additional pediatric patient cohorts and examined the effects of BRAF blockade in preclinical models of BRAF(V600E) and wild-type BRAF MA.BRAF(V600E) mutation status was examined in two pediatric MA patient cohorts. For functional studies, BRAF(V600E) MA cell lines were used to investigate the effects of BRAF shRNA knockdown in vitro, and to investigate BRAF pharmacologic inhibition in vitro and in vivo.BRAF(V600E) mutations were identified in 11 and 10% of MAs from two distinct series of tumors (six of 58 cases total). BRAF was expressed in all MA cell lines examined, among which BRAF(V600E) was identified in four instances. Using the BRAF(V600E)-specific inhibitor PLX4720, pharmacologic blockade of BRAF revealed preferential antiproliferative activity against BRAF(V600E) mutant cells in vitro, in contrast to the use of shRNA-mediated knockdown of BRAF, which inhibited cell growth of glioma cell lines regardless of BRAF mutation status. Using orthotopic MA xenografts, we show that PLX4720 treatment decreases tumor growth and increases overall survival in mice-bearing BRAF(V600E) mutant xenografts, while being ineffective, and possibly tumor promoting, against xenografts with wild-type BRAF.Our results indicate a 10% incidence of activating BRAF(V600E) among pediatric MAs. With regard to implications for therapy, our results support evaluation of BRAF(V600E)-specific inhibitors for treating BRAF(V600E) MA patients.

  View details for DOI 10.1158/1078-0432.CCR-11-1456

  View details for PubMedID 22038996

  View details for PubMedCentralID PMC3638050

• Mechanistic analysis of a DNA damage-induced, PTEN-dependent size checkpoint in human cells. Molecular and cellular biology Kim, J. S., Xu, X., Li, H., Solomon, D., Lane, W. S., Jin, T., Waldman, T. 2011; 31 (13): 2756-71

  Abstract

  Following DNA damage, human cells undergo arrests in the G(1) and G(2) phases of the cell cycle and a simultaneous arrest in cell size. We previously demonstrated that the cell size arrest can be uncoupled from the cell cycle arrest by mutational inactivation of the PTEN tumor suppressor gene. Here we show that the cell size checkpoint is inducible by DNA-damaging chemotherapeutic agents as well as by ionizing radiation and is effectively regulated by PTEN but not by its oncogenic counterpart, PIK3CA. Mutational analysis of PTEN and pharmacological inhibition of Akt revealed that modulation of Akt phosphorylation is unnecessary for cell size checkpoint control. To discover putative PTEN regulators and/or effectors involved in size checkpoint control, we employed a novel endogenous epitope tagging (EET) approach, which revealed that endogenous PTEN interacts at the membrane with an actin-remodeling complex that includes actin, gelsolin, and EPLIN. Pharmacological inhibition of actin remodeling in PTEN(+/+) cells recapitulated the lack of size checkpoint control seen in PTEN(-/-) cells. Taken together, these results provide further support for the existence of a DNA damage-inducible size checkpoint that is regulated by a major tumor suppressor, and they provide a novel Akt-independent mechanism by which PTEN controls cell size.

  View details for DOI 10.1128/MCB.01323-10

  View details for PubMedID 21536651

  View details for PubMedCentralID PMC3133370

• Integrated genomic analyses identify ERRFI1 and TACC3 as glioblastoma-targeted genes. Oncotarget Duncan, C. G., Killela, P. J., Payne, C. A., Lampson, B., Chen, W. C., Liu, J., Solomon, D., Waldman, T., Towers, A. J., Gregory, S. G., McDonald, K. L., McLendon, R. E., Bigner, D. D., Yan, H. 2010; 1 (4): 265-77

  Abstract

  The glioblastoma genome displays remarkable chromosomal aberrations, which harbor critical glioblastoma-specific genes contributing to several oncogenetic pathways. To identify glioblastoma-targeted genes, we completed a multifaceted genome-wide analysis to characterize the most significant aberrations of DNA content occurring in glioblastomas. We performed copy number analysis of 111 glioblastomas by Digital Karyotyping and Illumina BeadChip assays and validated our findings using data from the TCGA (The Cancer Genome Atlas) glioblastoma project. From this study, we identified recurrent focal copy number alterations in 1p36.23 and 4p16.3. Expression analyses of genes located in the two regions revealed genes which are dysregulated in glioblastomas. Specifically, we identify EGFR negative regulator, ERRFI1, within the minimal region of deletion in 1p36.23. In glioblastoma cells with a focal deletion of the ERRFI1 locus, restoration of ERRFI1 expression slowed cell migration. Furthermore, we demonstrate that TACC3, an Aurora-A kinase substrate, on 4p16.3, displays gain of copy number, is overexpressed in a glioma-grade-specific pattern, and correlates with Aurora kinase overexpression in glioblastomas. Our multifaceted genomic evaluation of glioblastoma establishes ERRFI1 as a potential candidate tumor suppressor gene and TACC3 as a potential oncogene, and provides insight on targets for oncogenic pathway-based therapy.

  View details for DOI 10.18632/oncotarget.137

  View details for PubMedID 21113414

  View details for PubMedCentralID PMC2992381

• IDH1(R132) mutation identified in one human melanoma metastasis, but not correlated with metastases to the brain. Biochemical and biophysical research communications Lopez, G. Y., Reitman, Z. J., Solomon, D., Waldman, T., Bigner, D. D., McLendon, R. E., Rosenberg, S. A., Samuels, Y., Yan, H. 2010; 398 (3): 585-7

  Abstract

  Isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) are enzymes which convert isocitrate to alpha-ketoglutarate while reducing nicotinamide adenine dinucleotide phosphate (NADP+to NADPH). IDH1/2 were recently identified as mutated in a large percentage of progressive gliomas. These mutations occur at IDH1(R132) or the homologous IDH2(R172). Melanomas share some genetic features with IDH1/2-mutated gliomas, such as frequent TP53 mutation. We sought to test whether melanoma is associated with IDH1/2 mutations. Seventy-eight human melanoma samples were analyzed for IDH1(R132) and IDH2(R172) mutation status. A somatic, heterozygous IDH1 c.C394T (p.R132C) mutation was identified in one human melanoma metastasis to the lung. Having identified this mutation in one metastasis, we sought to test the hypothesis that certain selective pressures in the brain environment may specifically favor the cell growth or survival of tumor cells with mutations in IDH1/2, regardless of primary tumor site. To address this, we analyzed IDH1(R132) and IDH2(R172) mutation status 53 metastatic brain tumors, including nine melanoma metastases. Results revealed no mutations in any samples. This lack of mutations would suggest that mutations in IDH1(R132) or IDH2(R172) may be necessary for the formation of tumors in a cell-lineage dependent manner, with a particularly strong selective pressure for mutations in progressive gliomas; this also suggests the lack of a particular selective pressure for growth in brain tissue in general. Studies on the cell-lineages of tumors with IDH1/2 mutations may help clarify the role of these mutations in the development of brain tumors.

  View details for DOI 10.1016/j.bbrc.2010.06.125

  View details for PubMedID 20603105

  View details for PubMedCentralID PMC2987603

• Lack of inherited mutations of PTPRD in familial melanoma and melanoma-astrocytoma syndrome. Pigment cell & melanoma research Solomon, D. A., Kim, J. S., Yang, X. R., Tucker, M. A., Goldstein, A. M., Samuels, Y., Waldman, T. 2009; 22 (4): 489-91

  View details for DOI 10.1111/j.1755-148X.2009.00587.x

  View details for PubMedID 19500277

  View details for PubMedCentralID PMC2758084

• Retinoblastoma/p107/p130 pocket proteins: protein dynamics and interactions with target gene promoters. The Journal of biological chemistry Stengel, K. R., Thangavel, C., Solomon, D. A., Angus, S. P., Zheng, Y., Knudsen, E. S. 2009; 284 (29): 19265-71

  Abstract

  The retinoblastoma (RB) tumor suppressor and its family members, p107 and p130, function by repressing E2F transcription factor activity to limit the expression of genes required for cell cycle progression. Traditionally, it is thought that the RB family proteins repress E2F target gene expression through complexing with E2F at gene promoters. However, whereas chromatin immunoprecipitation experiments have demonstrated p107 and p130 at E2F-responsive promoters, RB chromatin association has not been reliably observed. Here we used green fluorescent protein-tagged proteins to rigorously explore the mechanism of RB-mediated transcriptional repression relative to its p107 and p130 family members. The use of live cell fluorescent imaging demonstrated that RB, p107, and p130 exhibit similar nuclear dynamics. Although these findings suggest a similar engagement with nuclear structures, chromatin immunoprecipitation approaches with multiple independent antibodies failed to detect the association of RB with target gene promoters. However, by employing antibodies directed against green fluorescent protein, we could utilize the same antibody to assess RB, p107, and p130 engagement. This approach demonstrated RB association with target gene promoters in a fashion analogous to p107 and p130. Extension of this technology demonstrated that direct RB phosphorylation disrupts promoter association to regulate transcription. Thus, RB is associated with promoters in a manner similar to p107/p130 and that association is modulated by phosphorylation during cell cycle progression.

  View details for DOI 10.1074/jbc.M808740200

  View details for PubMedID 19279001

  View details for PubMedCentralID PMC2740551

• Sample type bias in the analysis of cancer genomes. Cancer research Solomon, D. A., Kim, J. S., Ressom, H. W., Sibenaller, Z., Ryken, T., Jean, W., Bigner, D., Yan, H., Waldman, T. 2009; 69 (14): 5630-3

  Abstract

  There is widespread agreement that cancer gene discovery requires high-quality tumor samples. However, whether primary tumors or cultured samples are superior for cancer genomics has been a longstanding subject of debate. This debate has recently become more important because federally funded cancer genomics has been centralized under The Cancer Genome Atlas, which has chosen to focus exclusively on primary tumors. Here, we provide a data-driven "perspective" on the effect of sample type selection on cancer genomics research. We show that, in the case of glioblastoma multiforme, primary tumors and xenografts are best for the identification of amplifications, whereas xenografts and cell lines are superior for the identification of homozygous deletions. We also note that many of the most important oncogenes and tumor suppressor genes have been discovered through the use of cell lines and xenografts, and highlight the lack of published evidence supporting the dogma that ex vivo culture generates artifactual genetic lesions. Based on this analysis, we suggest that cancer genomics projects such as The Cancer Genome Atlas should include a variety of sample types such as xenografts and cell lines in their integrated genomic analysis of cancer.

  View details for DOI 10.1158/0008-5472.CAN-09-1055

  View details for PubMedID 19567670

  View details for PubMedCentralID PMC3690469

• SWI/SNF deficiency results in aberrant chromatin organization, mitotic failure, and diminished proliferative capacity. Molecular biology of the cell Bourgo, R. J., Siddiqui, H., Fox, S., Solomon, D., Sansam, C. G., Yaniv, M., Muchardt, C., Metzger, D., Chambon, P., Roberts, C. W., Knudsen, E. S. 2009; 20 (14): 3192-9

  Abstract

  Switch (SWI)/sucrose nonfermentable (SNF) is an evolutionarily conserved complex with ATPase function, capable of regulating nucleosome position to alter transcriptional programs within the cell. It is known that the SWI/SNF complex is responsible for regulation of many genes involved in cell cycle control and proliferation, and it has recently been implicated in cancer development. The ATPase action of SWI/SNF is conferred through either the brahma-related gene 1 (Brg1) or brahma (Brm) subunit of the complex, and it is of central importance to the modification of nucleosome position. In this study, the role of the Brg1 and Brm subunits were examined as they relate to chromatin structure and organization. Deletion of the Brg1 ATPase results in dissolution of pericentromeric heterochromatin domains and a redistribution of histone modifications associated with these structures. This effect was highly specific to Brg1 and is not reproduced by the loss of Brm or SNF5/BAF47/INI1. Brg1 deficiency is associated with the appearance of micronuclei and aberrant mitoses that are a by-product of dissociated chromatin structure. Thus, Brg1 plays a critical role in maintaining chromatin structural integrity.

  View details for DOI 10.1091/mbc.e08-12-1224

  View details for PubMedID 19458193

  View details for PubMedCentralID PMC2710832

• Mutational inactivation of PTPRD in glioblastoma multiforme and malignant melanoma. Cancer research Solomon, D. A., Kim, J. S., Cronin, J. C., Sibenaller, Z., Ryken, T., Rosenberg, S. A., Ressom, H., Jean, W., Bigner, D., Yan, H., Samuels, Y., Waldman, T. 2008; 68 (24): 10300-6

  Abstract

  An additional tumor suppressor gene on chromosome 9p telomeric to the CDKN2A/B locus has long been postulated to exist. Using Affymetrix 250K single nucleotide polymorphism arrays to screen for copy number changes in glioblastoma multiforme (GBM), we detected a high frequency of deletions of the PTPRD gene, which encodes a receptor protein tyrosine phosphatase at chromosome 9p23-24.1. Missense and nonsense mutations of PTPRD were identified in a subset of the samples lacking deletions, including an inherited mutation with somatic loss of the wild-type allele. We then sequenced the gene in melanoma and identified 10 somatic mutations in 7 of 57 tumors (12%). Reconstitution of PTPRD expression in GBM and melanoma cells harboring deletions or mutations led to growth suppression and apoptosis that was alleviated by both the somatic and constitutional mutations. These data implicate PTPRD in the pathogenesis of tumors of neuroectodermal origin and, when taken together with other recent reports of PTPRD mutations in adenocarcinoma of the colon and lung, suggest that PTPRD may be one of a select group of tumor suppressor genes that are inactivated in a wide range of common human tumor types.

  View details for DOI 10.1158/0008-5472.CAN-08-3272

  View details for PubMedID 19074898

  View details for PubMedCentralID PMC2760967

• Conspirators in a capital crime: co-deletion of p18INK4c and p16INK4a/p14ARF/p15INK4b in glioblastoma multiforme. Cancer research Solomon, D. A., Kim, J. S., Jean, W., Waldman, T. 2008; 68 (21): 8657-60

  Abstract

  Glioblastoma multiforme (GBM) is one of the most dreaded cancer diagnoses due to its poor prognosis and the limited treatment options. Homozygous deletion of the p16(INK4a)/p14(ARF)/p15(INK4b) locus is among the most common genetic alterations in GBM. Two recent studies have shown that deletion and mutation of another INK4 family member, p18(INK4c), also drives the pathogenesis of GBM. This minireview will discuss the known roles for p18(INK4c) in the initiation and progression of cancer and suggest opportunities for future studies.

  View details for DOI 10.1158/0008-5472.CAN-08-2084

  View details for PubMedID 18974105

  View details for PubMedCentralID PMC2828676

• WAVE1 is required for oligodendrocyte morphogenesis and normal CNS myelination. The Journal of neuroscience : the official journal of the Society for Neuroscience Kim, H. J., DiBernardo, A. B., Sloane, J. A., Rasband, M. N., Solomon, D., Kosaras, B., Kwak, S. P., Vartanian, T. K. 2006; 26 (21): 5849-59

  Abstract

  Myelin formation involves the outgrowth of an oligodendrocyte cell process that can be regarded as a giant lamellipodium because it is an actively growing structure with extruded cytoplasm. The actin cytoskeleton is critical to morphogenesis, but little is known about regulation of actin dynamics in oligodendrocytes. Wiskott-Aldrich syndrome protein family verprolin homologous (WAVE) proteins mediate lamellipodia formation; thus, we asked whether these proteins function in oligodendrocyte process formation and myelination. Here, we show that WAVE1 is expressed by oligodendrocytes and localizes to the lamella leading edge where actin polymerization is actively regulated. CNS WAVE1 expression increases at the onset of myelination. Expression of dominant-negative WAVE1 impaired process outgrowth and lamellipodia formation in cultured oligodendrocytes. Similarly, oligodendrocytes isolated from mice lacking WAVE1 had fewer processes compared with controls, whereas neurons and astrocytes exhibited normal morphology. In white matter of WAVE1-/- mice, we found regional hypomyelination in the corpus callosum and to a lesser extent in the optic nerve. In optic nerve from WAVE1-/- mice, there were fewer nodes of Ranvier but nodal morphology was normal, implicating a defect in myelin formation. Our in vitro findings support a developmentally dynamic and cell-autonomous role for WAVE1 in regulating process formation in oligodendrocytes. Additionally, WAVE1 function during CNS myelination appears to be linked to regional cues. Although its loss can be compensated for in many CNS regions, WAVE1 is clearly required for normal amounts of myelin to form in corpus callosum and optic nerve. Together, these data demonstrate a role for WAVE1 in oligodendrocyte morphogenesis and myelination.

  View details for DOI 10.1523/JNEUROSCI.4921-05.2006

  View details for PubMedID 16723544

  View details for PubMedCentralID PMC6675261

• Dynamic targeting of the replication machinery to sites of DNA damage. The Journal of cell biology Solomon, D. A., Cardoso, M. C., Knudsen, E. S. 2004; 166 (4): 455-63

  Abstract

  Components of the DNA replication machinery localize into discrete subnuclear foci after DNA damage, where they play requisite functions in repair processes. Here, we find that the replication factors proliferating cell nuclear antigen (PCNA) and RPAp34 dynamically exchange at these repair foci with discrete kinetics, and this behavior is distinct from kinetics during DNA replication. Posttranslational modification is hypothesized to target specific proteins for repair, and we find that accumulation and stability of PCNA at sites of damage requires monoubiquitination. Contrary to the popular notion that phosphorylation on the NH2 terminus of RPAp34 directs the protein for repair, we demonstrate that phosphorylation by DNA-dependent protein kinase enhances RPAp34 turnover at repair foci. Together, these findings support a dynamic exchange model in which multiple repair factors regulated by specific modifications have access to and rapidly turn over at sites of DNA damage.

  View details for DOI 10.1083/jcb.200312048

  View details for PubMedID 15314062

  View details for PubMedCentralID PMC2172213

• Hierarchical requirement of SWI/SNF in retinoblastoma tumor suppressor-mediated repression of Plk1. The Journal of biological chemistry Gunawardena, R. W., Siddiqui, H., Solomon, D. A., Mayhew, C. N., Held, J., Angus, S. P., Knudsen, E. S. 2004; 279 (28): 29278-85

  Abstract

  Plk1 (Polo-like kinase 1) is a critical regulator of cell cycle progression that harbors oncogenic activity and exhibits aberrant expression in multiple tumors. However, the mechanism through which Plk1 expression is regulated has not been extensively studied. Here we demonstrate that Plk1 is a target of the retinoblastoma tumor suppressor (RB) pathway. Activation of RB and related pocket proteins p107/p130 mediate attenuation of Plk1. Conversely, RB loss deregulates the control of Plk1 expression. RB pathway activation resulted in the repression of Plk1 promoter activity, and this action was dependent on the SWI/SNF chromatin remodeling complex. Although SWI/SNF subunits are lost during tumorigenesis and cooperate with RB for transcriptional repression, the mechanism through which SWI/SNF impinges on RB action is unresolved. Therefore, we delineated the requirement of SWI/SNF for three critical facets of Plk1 promoter regulation: transcription factor binding, corepressor binding, and histone modification. We find that E2F4 and pocket protein association with the Plk1 promoter is independent of SWI/SNF. However, these analyses revealed that SWI/SNF is required for histone deacetylation of the Plk1 promoter. The importance of SWI/SNF-dependent histone deacetylation of the Plk1 promoter was evident, because blockade of this event restored Plk1 expression in the presence of active RB. In summary, these data demonstrate that Plk1 is a target of the RB pathway. Moreover, these findings demonstrate a hierarchical role for SWI/SNF in the control of promoter activity through histone modification.

  View details for DOI 10.1074/jbc.M400395200

  View details for PubMedID 15105433

• Analysis of RB action in DNA damage checkpoint response. Methods in molecular biology (Clifton, N.J.) Mayhew, C. N., Bosco, E. E., Solomon, D. A., Knudsen, E. S., Angus, S. P. 2004; 281: 3-16

  Abstract

  Cell cycle checkpoints play a key role in maintaining genome stability by monitoring the order and integrity of cell division events. Checkpoints induced by DNA damage function to limit the propagation of potentially deleterious mutations. The retinoblastoma tumor suppressor (RB) is a critical effector of DNA damage checkpoint function by eliciting G1-phase cell cycle arrest following genotoxic stress. Here, we describe methodologies for evaluation of three facets of RB action in the DNA damage checkpoint response: (1) transcriptional repression of E2F-regulated genes (cyclin A reporter assay); (2) induction of cell cycle arrest (Brd-U incorporation assay); and (3) inhibition of DNA double-strand break accumulation (phosphorylated-histone H2A.X detection). Together, this combination of techniques allows the evaluation of RB action in the coordinated checkpoint response to DNA damage.

  View details for DOI 10.1385/1-59259-811-0:003

  View details for PubMedID 15220518

• RB reversibly inhibits DNA replication via two temporally distinct mechanisms. Molecular and cellular biology Angus, S. P., Mayhew, C. N., Solomon, D. A., Braden, W. A., Markey, M. P., Okuno, Y., Cardoso, M. C., Gilbert, D. M., Knudsen, E. S. 2004; 24 (12): 5404-20

  Abstract

  The retinoblastoma (RB) tumor suppressor is a critical negative regulator of cellular proliferation. Repression of E2F-dependent transcription has been implicated as the mechanism through which RB inhibits cell cycle progression. However, recent data have suggested that the direct interaction of RB with replication factors or sites of DNA synthesis may contribute to its ability to inhibit S phase. Here we show that RB does not exert a cis-acting effect on DNA replication. Furthermore, the localization of RB was distinct from replication foci in proliferating cells. While RB activation strongly attenuated the RNA levels of multiple replication factors, their protein expression was not diminished coincident with cell cycle arrest. During the first 24 h of RB activation, components of the prereplication complex, initiation factors, and the clamp loader complex (replication factor C) remained tethered to chromatin. In contrast, the association of PCNA and downstream components of the processive replication machinery was specifically disrupted. This signaling from RB occurred in a manner dependent on E2F-mediated transcriptional repression. Following long-term activation of RB, we observed the attenuation of multiple replication factors, the complete cessation of DNA synthesis, and impaired replicative capacity in vitro. Therefore, functional distinctions exist between the "chronic" RB-mediated arrest state and the "acute" arrest state. Strikingly, attenuation of RB activity reversed both acute and chronic replication blocks. Thus, continued RB action is required for the maintenance of two kinetically and functionally distinct modes of replication inhibition.

  View details for DOI 10.1128/MCB.24.12.5404-5420.2004

  View details for PubMedID 15169903

  View details for PubMedCentralID PMC419877

• Retinoblastoma tumor suppressor: analyses of dynamic behavior in living cells reveal multiple modes of regulation. Molecular and cellular biology Angus, S. P., Solomon, D. A., Kuschel, L., Hennigan, R. F., Knudsen, E. S. 2003; 23 (22): 8172-88

  Abstract

  The retinoblastoma tumor suppressor, RB, assembles multiprotein complexes to mediate cell cycle inhibition. Although many RB binding partners have been suggested to underlie these functions, the validity of these interactions on the behavior of RB complexes in living cells has not been investigated. Here, we studied the dynamic behavior of RB by using green fluorescent protein-RB fusion proteins. Although these proteins were universally nuclear, phosphorylation or oncoprotein binding mediated their active exclusion from the nucleolus. In vivo imaging approaches revealed that RB exists in dynamic equilibrium between a highly mobile and a slower diffusing species, and genetic lesions associated with tumorigenesis increased the fraction of RB in a highly mobile state. The RB complexes dictating cell cycle arrest were surprisingly dynamic and harbored a relatively short residence time on chromatin. In contrast, this rapid exchange was attenuated in cells that are hypersensitive to RB, suggesting that responsiveness may inversely correlate with mobility. The stability of RB dynamics within the cell was additionally modified by the presence and function of critical corepressors. Last, the RB-assembled complexes present in living cells were primarily associated with E2F binding sites in chromatin. In contrast to RB, E2F1 consistently maintained a stable association with E2F sites regardless of cell type. Together, these results elucidate the kinetic framework of RB tumor suppressor action in transcriptional repression and cell cycle regulation.

  View details for DOI 10.1128/MCB.23.22.8172-8188.2003

  View details for PubMedID 14585976

  View details for PubMedCentralID PMC262398

• Histone deacetylation of RB-responsive promoters: requisite for specific gene repression but dispensable for cell cycle inhibition. Molecular and cellular biology Siddiqui, H., Solomon, D. A., Gunawardena, R. W., Wang, Y., Knudsen, E. S. 2003; 23 (21): 7719-31

  Abstract

  The retinoblastoma tumor suppressor protein (RB) is targeted for inactivation in the majority of human tumors, underscoring its critical role in attenuating cellular proliferation. RB inhibits proliferation by repressing the transcription of genes that are essential for cell cycle progression. To repress transcription, RB assembles multiprotein complexes containing chromatin-modifying enzymes, including histone deacetylases (HDACs). However, the extent to which HDACs participate in transcriptional repression and are required for RB-mediated repression has not been established. Here, we investigated the role of HDACs in RB-dependent cell cycle inhibition and transcriptional repression. We find that active RB mediates histone deacetylation on cyclin A, Cdc2, topoisomerase IIalpha, and thymidylate synthase promoters. We also demonstrate that this deacetylation is HDAC dependent, since the HDAC inhibitor trichostatin A (TSA) prevented histone deacetylation at each promoter. However, TSA treatment blocked RB repression of only a specific subset of genes, thereby demonstrating that the requirement of HDACs for RB-mediated transcriptional repression is promoter specific. The HDAC-independent repression was not associated with DNA methylation or gene silencing but was readily reversible. We show that this form of repression resulted in altered chromatin structure and was dependent on SWI/SNF chromatin remodeling activity. Importantly, we find that cell cycle inhibitory action of RB is not intrinsically dependent on the ability to recruit HDAC activity. Thus, while HDACs do play a major role in RB-mediated repression, they are dispensable for the repression of critical targets leading to cell cycle arrest.

  View details for DOI 10.1128/MCB.23.21.7719-7731.2003

  View details for PubMedID 14560017

  View details for PubMedCentralID PMC207566

• Growth factor control of CNS myelination. Developmental neuroscience Park, S. K., Solomon, D., Vartanian, T. 2001; 23 (4-5): 327-37

  Abstract

  The molecular signals required for initiating myelination and maintenance of the myelin internode are not known. Several growth factor families have been implicated in promoting oligodendrocyte survival or differentiation and may have consequences on formation of myelin. We developed a reliable assay for detecting ensheathment of neurites by oligodendrocytes in spinal cord explants. This system was used to assay the effect of selected growth factors on myelin internode formation. We examined the influence on myelination of the polypeptide growth factors neuregulin (NRG), platelet-derived growth factor (PDGF), leukemia inhibitory factor (LIF), and the thyroid hormone T(3). We found that NRG, PDGF, and T(3) treatments enhanced myelination while LIF treatment inhibited it. We furthermore found that the most potent combination of factors to enhance myelination was NRG and T(3). Our results demonstrate that the role of growth factors on CNS myelination can be reliably studied in a controlled in vitro environment and that the impact of individual or combinations of growth factors on myelination cannot be predicted by their known effects on oligodendrocyte survival, proliferation, or differentiation.

  View details for DOI 10.1159/000048716

  View details for PubMedID 11756748