Rohit Gupta

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

• DNA MUTATION SEQUENCING AND METHYLATION ANALYSIS OF SOMATICNF1 MUTANT IDH-WILDTYPE GLIOBLASTOMA IDENTIFIES THREE EPIGENETIC GROUPS ANDCDKN2A/B LOSS AS A NEGATIVE PROGNOSTIC BIOMARKER Mirchia, K., Pan, S., Payne, E., Liu, J., Peeran, Z., Shukla, P., Young, J., Gupta, R., Wu, J., Pak, J., Seo, K., Ozawa, T., Na, B., Reddy, A., Braunstein, S., Phillips, J., Chang, S., Solomon, D., Perry, A., Raleigh, D., Berger, M., Abate, A., Vasudevan, H. OXFORD UNIV PRESS INC. 2024

  View details for DOI 10.1093/neuonc/noae165.0752

  View details for Web of Science ID 001362477500017

• SINGLE-CELL RNA (SCRNA) SEQUENCING OF PAIRED PRIMARY AND RECURRENT ATYPICAL TERATOID/RHABDOID TUMORS (AT/RT) REVEALED MOLECULAR DIFFERENCES AND THERAPY-RESISTANT PRIMARY TUMOR CELLS Altendorf, L., Roy, R., de Faria, F. W., Hack, K., Koch, A., Schuhmann, M. U., Hauser, P., Johann, P. D., Hasselblatt, M., Kerl, K., Fruehwald, M. C., Schueller, U. OXFORD UNIV PRESS INC. 2024

  View details for DOI 10.1093/neuonc/noae165.0721

  View details for Web of Science ID 001362489500009

• "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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• Isolation of PBMCs Using Vacutainer® Cellular Preparation Tubes Bio-protocol Puleo, A., Carroll, C., Maecker, H., Gupta, R. 2017; 7 (2)

  View details for DOI 10.21769/BioProtoc.2103

• Hypermutation of DPYD Deregulates Pyrimidine Metabolism and Promotes Malignant Progression. Molecular cancer research : MCR Edwards, L., Gupta, R., Filipp, F. V. 2016; 14 (2): 196-206

  Abstract

  New strategies are needed to diagnose and target human melanoma. To this end, genomic analyses was performed to assess somatic mutations and gene expression signatures using a large cohort of human skin cutaneous melanoma (SKCM) patients from The Cancer Genome Atlas (TCGA) project to identify critical differences between primary and metastatic tumors. Interestingly, pyrimidine metabolism is one of the major pathways to be significantly enriched and deregulated at the transcriptional level in melanoma progression. In addition, dihydropyrimidine dehydrogenase (DPYD) and other important pyrimidine-related genes: DPYS, AK9, CAD, CANT1, ENTPD1, NME6, NT5C1A, POLE, POLQ, POLR3B, PRIM2, REV3L, and UPP2 are significantly enriched in somatic mutations relative to the background mutation rate. Structural analysis of the DPYD protein dimer reveals a potential hotspot of recurring somatic mutations in the ligand-binding sites as well as the interfaces of protein domains that mediated electron transfer. Somatic mutations of DPYD are associated with upregulation of pyrimidine degradation, nucleotide synthesis, and nucleic acid processing while salvage and nucleotide conversion is downregulated in TCGA SKCM.At a systems biology level, somatic mutations of DPYD cause a switch in pyrimidine metabolism and promote gene expression of pyrimidine enzymes toward malignant progression.

  View details for DOI 10.1158/1541-7786.MCR-15-0403

  View details for PubMedID 26609109

  View details for PubMedCentralID PMC5024535

• Cancer systems biology of TCGA SKCM: efficient detection of genomic drivers in melanoma. Scientific reports Guan, J., Gupta, R., Filipp, F. V. 2015; 5: 7857

  Abstract

  We characterized the mutational landscape of human skin cutaneous melanoma (SKCM) using data obtained from The Cancer Genome Atlas (TCGA) project. We analyzed next-generation sequencing data of somatic copy number alterations and somatic mutations in 303 metastatic melanomas. We were able to confirm preeminent drivers of melanoma as well as identify new melanoma genes. The TCGA SKCM study confirmed a dominance of somatic BRAF mutations in 50% of patients. The mutational burden of melanoma patients is an order of magnitude higher than of other TCGA cohorts. A multi-step filter enriched somatic mutations while accounting for recurrence, conservation, and basal rate. Thus, this filter can serve as a paradigm for analysis of genome-wide next-generation sequencing data of large cohorts with a high mutational burden. Analysis of TCGA melanoma data using such a multi-step filter discovered novel and statistically significant potential melanoma driver genes. In the context of the Pan-Cancer study we report a detailed analysis of the mutational landscape of BRAF and other drivers across cancer tissues. Integrated analysis of somatic mutations, somatic copy number alterations, low pass copy numbers, and gene expression of the melanogenesis pathway shows coordination of proliferative events by Gs-protein and cyclin signaling at a systems level.

  View details for DOI 10.1038/srep07857

  View details for PubMedID 25600636

  View details for PubMedCentralID PMC4298731