Dr. Kebebew is an internationally recognized expert in Endocrine Oncology and Surgery. He has performed more than three thousand operations on the adrenal, parathyroid and thyroid glands, and for neuroendocrine tumors of the gastrointestinal tract and pancreas.
Dr. Kebebew has published over 400 articles, chapters and textbooks, and serves on the editorial board and as a reviewer for 54 biomedical journals. He has received awards from the American Cancer Society, American Association for Cancer Research, American Thyroid Association, American Association of Endocrine Surgeons, and International Association of Endocrine Surgeons.
- Thyroid Cancer/Nodules
- Thyroid Surgery
- Parathyroid Surgery
- Endocrine Surgery
- Endocrine Tumors
- Neuroendocrine tumors of the gastrointestinal tract and pancreas
- Adrenalectomy/Adrenal Surgery
- Adrenal Tumors
- Primary hyperaldosteronism
- Adrenal Cushing's syndrome
- General Surgery
Board Certification: General Surgery, American Board of Surgery (2003)
Residency:UCSF General Surgery Residency (2002) CA
Postdoctoral training, NCI T32 fellowship, Cancer Biology (1998)
Medical Education:University of California at San Francisco School of Medicine (1995) CA
Current Research and Scholarly Interests
Dr. Kebebew’s translational and clinical investigations have three main scientific goals: 1) to develop effective therapies for fatal, rare and neglected endocrine cancers, 2) to identify new methods, strategies and technologies for improving the diagnosis and treatment of endocrine neoplasms and the prognostication of endocrine cancers, and 3) to develop methods for precision treatment of endocrine tumors.
Association of Thyrotropin Suppression With Survival Outcomes in Patients With Intermediate- and High-Risk Differentiated Thyroid Cancer.
JAMA network open
2019; 2 (2): e187754
Importance: Suppression of thyrotropin (often referred to as thyroid-stimulating hormone, or TSH) with levothyroxine used in management of intermediate- and high-risk differentiated thyroid cancer (DTC) to reduce the likelihood of progression and death is based on conflicting evidence.Objective: To examine a cohort of patients with intermediate- and high-risk DTC to assess the association of thyrotropin suppression with progression-free survival (PFS) and overall survival.Design, Setting, and Participants: This cohort study used a multicenter database analysis including patients from tertiary referral centers and local clinics followed up for a mean (SD) of 7.2 (5.8) years. Patients with DTC treated uniformly with total thyroidectomy and radioactive iodine between January 1, 1979, and March 1, 2015, were included. Among the 1012 patients, 145 patients were excluded due to the lack of longitudinal thyrotropin measurements.Exposures: Levothyroxine therapy to target thyrotropin suppression with dose adjustments based on changing thyrotropin goal.Main Outcomes and Measures: The primary outcome measures were overall survival and PFS. A Cox proportional hazards model was used to assess the contribution of age, sex, tumor size, histology, and lymph node and distant metastases at landmarks 1.5, 3.0, and 5.0 years. The patients were divided into 3 groups based on mean thyrotropin score before each landmark: (1) suppressed thyrotropin, (2) moderately suppressed or low-normal thyrotropin, and (3) low-normal or elevated thyrotropin.Results: Among 867 patients (557 [64.2%] female; mean [SD] age, 48.5 [16.5] years) treated with a median (range) cumulative dose of 151 (30-1600) mCi radioactive iodine, disease progression was observed in 293 patients (33.8%), and 34 patients (3.9%) died; thus, the study was underpowered in death events. Thyrotropin suppression was not associated with improved PFS at landmarks 1.5 (P=.41), 3.0 (P=.51), and 5.0 (P=.64) years. At 1.5 and 3.0 years, older age (hazard ratio [HR], 1.06; 95% CI, 1.03-1.08 and HR, 1.05; 95% CI, 1.01-1.08, respectively), lateral neck lymph node metastases (HR, 4.64; 95% CI, 2.00-10.70 and HR, 4.02; 95% CI, 1.56-10.40, respectively), and distant metastases (HR, 7.54; 95% CI, 3.46-16.50 and HR, 7.10; 95% CI, 2.77-18.20, respectively) were independently associated with subsequent time to progression, while at 5.0 years, PFS was shorter for patients with lateral neck lymph node metastases (HR, 3.70; 95% CI, 1.16-11.90) and poorly differentiated histology (HR, 71.80; 95% CI, 9.80-526.00).Conclusions and Relevance: Patients with intermediate- and high-risk DTC might not benefit from thyrotropin suppression. This study provides the justification for a randomized trial.
View details for PubMedID 30707227
Risk Haplotypes Uniquely Associated with Radioiodine Refractory Thyroid Cancer Patients of High African Ancestry.
Thyroid : official journal of the American Thyroid Association
BACKGROUND: Thyroid cancer patients with radioiodine refractory (RAI-R) disease, resulting from insufficient RAI delivery and/or RAI resistance, have increased mortality and limited treatment options. To date, studies have largely focused on tumor mutations associated with different stages of disease, which could provide prognostic value for RAI-R disease. We hypothesize that germline variants contributing to intrinsic differences in iodine metabolism, tumor microenvironment and/or immune surveillance are associated with RAI-R disease.METHODS: Whole-genome genotyping data analysis was performed on 1,145 Caucasian (CAU) patients, 244 of whom were RAI-R, and 55 African American (AA) patients, 9 of whom were RAI-R. Germline variant association studies were conducted using candidate genes involved in iodine metabolism or DNA-damage repair, as well as genome-wide association analysis. Initial data indicated several notable variants in a small number of patients (N=7), who were later determined to be AA patients of >80% African ancestry (N=37). This prompted us to focus on germline SNPs uniquely associated with RAI-R AA patients. Sanger sequencing was performed to validate risk alleles and identify the incidence of common somatic mutations BRAFV600E, NRASQ61R, and HRASQ61R, in AA patients whose primary tumor samples were available (N=28/55).RESULTS: We identified TG, BRCA1 and NSMCE2 haplotypes uniquely associated with RAI-R AA patients of >80% African ancestry. All patients with the TG haplotype (N=4) had a biochemical incomplete response to RAI therapy. Patients with the NSMCE2 haplotype (N=4) were diagnosed at a young age (13, 17, 17, and 26 years old) with distant metastatic disease at initial diagnosis. The BRCA1 haplotype co-occurred in 3/4 patients with the NSMCE2 haplotype. The incidence of BRAFV600E appears lower in papillary thyroid carcinoma (PTC) from AA patients of >80% African ancestry (N=3/14, 21%) than in AA patients of <80% African ancestry (N=6/9, 67%), albeit only approaching statistical significance (p=0.077). The tumors available from three RAI-R AA patients were negative for BRAFV600E, NRASQ61R, HRASQ61R.CONCLUSIONS: The identification of candidate RAI-R risk haplotypes may allow early stratification of clinical manifestations of RAI-R disease followed by early intervention and personalized treatment strategies. Functional annotation of candidate RAI-R risk haplotypes may provide insight into the mechanisms underlying RAI-R disease.
View details for PubMedID 30654714
Distinct genome-wide methylation patterns in sporadic and hereditary nonfunctioning pancreatic neuroendocrine tumors.
BACKGROUND: Aberrant methylation is a known cause of cancer initiation and/or progression. There are scant data on the genome-wide methylation pattern of nonfunctioning pancreatic neuroendocrine tumors (NFPanNETs) and sporadic and hereditary NFPanNETs.METHODS: Thirty-three tissue samples were analyzed: they included samples from sporadic (n=9), von Hippel-Lindau (VHL)-related (n=10), and multiple endocrine neoplasia type 1 (MEN1)-related NFPanNETs (n=10) as well as normal islet cells (n=4) for comparison. Genome-wide CpG methylation profiling was performed with the Infinium MethylationEPIC BeadChip assay and was analyzed with R-based tools.RESULTS: In unsupervised hierarchical clustering, sporadic and MEN1-related NFPanNETs clustered together, and the VHL group was in a separate cluster. MEN1-related NFPanNETs had a higher rate of hypermethylated CpG sites in comparison with sporadic and VHL-related tumor groups. Differentially methylated region analysis confirmed the higher rate of hypermethylation in MEN1-related tumors. Moreover, in an integrated analysis of gene expression data for the same tumor samples, downregulated gene expression was found in most genes that were hypermethylated. In a CpG island methylator phenotype analysis, 3 genes were identified and confirmed to have downregulated gene expression: secreted frizzle-related protein 5 (SFRP5) in sporadic NFPanNETs and cell division cycle-associated 7-like (CDCA7L) and RNA binding motif 47 (RBM47) in MEN1-related NFPanNETs.CONCLUSIONS: MEN1 NFPanNETs have a higher rate of geno me-wide hypermethylation than other NFPanNET subtypes. The similarity between the pathways enriched in a methylation analysis of known genes involved in NFPanNET tumorigenesis suggests a key role for aberrant methylation in the pathogenesis of NFPanNETs.
View details for PubMedID 30620390
Curbing Unnecessary and Wasted Diagnostic Imaging.
View details for PubMedID 30615023
Lysyl Oxidase is a key player in BRAF/MAPK pathway-driven thyroid cancer aggressiveness.
Thyroid : official journal of the American Thyroid Association
BACKGROUND: BRAF mutation is the most common somatic mutation in thyroid cancer. The mechanism associated with BRAF mutant tumor aggressiveness remains unclear. Lysyl oxidase (LOX) is highly expressed in aggressive thyroid cancers, and involved in cancer metastasis. The objective is to determine whether LOX mediates the effect of the activated MAPK pathway in thyroid cancer.METHODS: The prognostic value of LOX and its association with BRAF mutation was analyzed in the TCGA and an independent cohort. Inhibition of mutant BRAF and the MAPK pathway, and overexpression of BRAF mutant and mouse models of BRAFV600E were used to test the effect on LOX expression.RESULTS: In the TCGA cohort, LOX expression was higher in BRAF mutant tumors compared to wild-type tumors (P<0.0001).Patients with BRAF mutant tumors with high LOX expression had a shorter disease-free survival (DFS) (P=0.03) compared to patients with BRAF mutation and low LOX group. In the independent cohort, a significant positive correlation between LOX and percentage of BRAF mutated cells was found. The independent cohort confirmed high LOX expression to be associated with a shorter DFS (P=0.01). Inhibition of BRAFV600E and MEK decreased LOX expression. Conversely overexpression of mutant BRAF increased LOX expression. The mice with thyroid-specific expression of BRAFV600E, showed a strong LOX and p-ERK expressions in tumor tissue. Inhibition of BRAFV600E in transgenic and orthotopic mouse models significantly reduced the tumor burden as well as LOX and p-ERK expressions.CONCLUSIONS: Our data suggests that BRAFV600E tumors with high LOX expression are associated with more aggressive disease. The biological underpinnings of the clinical findings were confirmed by showing that BRAF and the MAPK pathway regulate LOX expression.
View details for PubMedID 30398411
ASO Author Reflections: Systemic Inflammatory Markers in Pancreatic Neuroendocrine Tumors.
Annals of surgical oncology
View details for PubMedID 30353397
Do patients with familial nonmedullary thyroid cancer present with more aggressive disease? Implications for initial surgical treatment.
BACKGROUND: There are conflicting reports on whether familial nonmedullary thyroid cancer is more aggressive than sporadic nonmedullary thyroid cancer. Our aim was to determine if the clinical and pathologic characteristics of familial nonmedullary thyroid cancer are different than nonmedullary thyroid cancer.METHODS: We compared patients with familial nonmedullary thyroid cancer to a cohort of 53,571 nonmedullary thyroid cancer patients from the Surveillance, Epidemiology, and End Results database.RESULTS: A total of 78 patients with familial nonmedullary thyroid cancer from 31 kindreds presented at a younger age (P = .04) and had a greater rate of T1 disease (P = .019), lymph node metastasis (P = .002), and the classic variant of papillary thyroid cancer on histology (P < .001) compared with the Surveillance, Epidemiology, and End Results cohort. Patients with ≥3 affected family members presented at a younger age (P = .04), had a lesser female-to-male ratio (P = .04), and had a greater rate of lymph node metastasis (P = .009). Compared with the Surveillance, Epidemiology, and End Results cohort, we found a higher prevalence of lymph node metastasis in familial nonmedullary thyroid cancer index cases (P = .003) but not in those diagnosed by screening ultrasonography (P = .58).CONCLUSION: Patients with familial nonmedullary thyroid cancer present at a younger age and have a greater rate of lymph node metastasis. The treatment for familial nonmedullary thyroid cancer should be more aggressive in patients who present clinically and in those who have ≥3 first-degree relatives affected.
View details for PubMedID 30327187
Metastatic neuroendocrine tumors of the gastrointestinal tract and pancreas: A surgeon's plea to centering attention on the liver.
Seminars in oncology
Over 50% of patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have stage IV disease at presentation and the most likely organ to be affected by metastases is the liver. Hepatic involvement and hepatic tumor burden is a key prognostic factor affecting survival of these patients and 80% eventually die of liver failure due to tumor dissemination within the liver. This commentary explores the efficacy and limitations of systemic treatments in patients with GEP-NETs and liver metastases. Landmark randomized trials using systemic therapies including sandostatin (PROMID), lanreotide (CLARINET), everolimus (RADIANT 3 and 4), sunitinib and Peptide Receptor Radionuclide Therapy (NETTER-1) have not shown efficacy in reducing liver tumor burden in patients with stage IV GEP-NETs with liver metastases as outlined in this review. Although often overlooked, surgical debulking has been associated with a significant survival advantage in large retrospective studies and in our opinion should remain an important therapeutic option for patients with stage IV GEP-NETs and liver metastases.
View details for PubMedID 30318110
Cumulative Radiation Exposures from CT Screening and Surveillance Strategies for von Hippel-Lindau-associated Solid Pancreatic Tumors.
Purpose To assess the potential ionizing radiation exposure from CT scans for both screening and surveillance of patients with von Hippel-Lindau (VHL) syndrome. Materials and Methods For this retrospective study, abdomen-pelvic (AP) and chest-abdomen-pelvic (CAP) CT scans were performed with either a three-phase (n = 1242) or a dual-energy virtual noncontrast protocol (VNC; n = 149) in 747 patients with VHL syndrome in the National Institutes of Health Clinical Center between 2009 and 2015 (mean age, 47.6 years ± 14.6 [standard deviation]; age range, 12-83 years; 320 women [42.8%]). CT scanning parameters for patients with pancreatic neuroendocrine tumors (PNETs; 124 patients and 381 scans) were compared between a tumor diameter-based surveillance protocol and a VHL genotype and tumor diameter-based algorithm (a tailored algorithm) developed by three VHL clinicians. Organ and lifetime radiation doses were estimated by two radiologists and five radiation scientists. Cumulative radiation doses were compared between the PNET surveillance algorithms by analyses of variance, and a two-tailed P value less than .05 indicated statistical significance. Results Median cumulative colon doses for annual CAP and AP CT scans from age 15 to 40 years ranged from 0.34 Gy (5th-95th percentiles, 0.18-0.75; dual-energy VNC CT) to 0.89 Gy (5th-95th percentiles, 0.42-1.0; three-phase CT). For the current PNET surveillance protocol, the cumulative effective radiation dose from age 40 to 65 years was 682 mSv (tumors < 1.2 cm) and 2125 mSv (tumors > 3 cm). The tailored algorithm could halve these doses for patients with initial tumor diameter less than 1.2 cm (P < .001). Conclusion CT screening of patients with von Hippel-Lindau syndrome can lead to substantial radiation exposures, even with dual-energy virtual noncontrast CT. A genome and tumor diameter-based algorithm for pancreatic neuroendocrine tumor surveillance may potentially reduce lifetime radiation exposure. © RSNA, 2018 Online supplemental material is available for this article.
View details for PubMedID 30299237
Metastatic adrenocortical carcinoma displays higher mutation rate and tumor heterogeneity than primary tumors
2018; 9: 4172
Adrenocortical cancer (ACC) is a rare cancer with poor prognosis and high mortality due to metastatic disease. All reported genetic alterations have been in primary ACC, and it is unknown if there is molecular heterogeneity in ACC. Here, we report the genetic changes associated with metastatic ACC compared to primary ACCs and tumor heterogeneity. We performed whole-exome sequencing of 33 metastatic tumors. The overall mutation rate (per megabase) in metastatic tumors was 2.8-fold higher than primary ACC tumor samples. We found tumor heterogeneity among different metastatic sites in ACC and discovered recurrent mutations in several novel genes. We observed 37-57% overlap in genes that are mutated among different metastatic sites within the same patient. We also identified new therapeutic targets in recurrent and metastatic ACC not previously described in primary ACCs.
View details for PubMedID 30301885
Radioguided Surgery With Gallium 68 Dotatate for Patients With Neuroendocrine Tumors.
Importance: Neuroendocrine tumors (NETs) express somatostatin receptors, which can be targeted with radiolabeled peptides. In a variety of solid tumors, radioguided surgery (RGS) has been used to guide surgical resection. Gallium 68 (68Ga) dota peptides have been shown to be more accurate than other radioisotopes for detecting NETs. A pilot study previously demonstrated the feasibility and safety of 68Ga-dotatate RGS for patients with NETs.Objective: To evaluate what intraoperative techniques and thresholds define positive lesions that warrant resection during 68Ga-dotatate RGS.Design, Setting, and Participants: This prospective cohort study, conducted between October 23, 2013, and February 14, 2018, included 44 patients with NETs who underwent 68Ga-dotatate RGS.Intervention: Gallium 68-dotatate RGS.Main Outcomes and Measures: The in vivo and ex vivo tumor to background ratio (TBR) was assessed for resected lesions and correlated with the histopathologic findings.Results: Forty-four patients (22 women and 22 men; mean [SD] age, 51.0 [13.7] years) had 133 lesions detected on preoperative imaging scans, with a diagnosis of a pancreatic NET (19 of 44 [43%]), gastrointestinal NET (22 of 44 [50%]), and pheochromocytoma or paraganglioma (3 of 44 [7%]). The TBR was obtained by normalizing to the omentum (106 of 133 [79.7%]) or other solid organs (27 of 133 [20.3%]). The omentum had a significantly lower mean (SD) count than other solid organs for background count activity 3 hours after injection (22.1 [17.0] vs 34.5 [39.0]; P<.001). The lesions containing NETs had a higher TBR than those that did not contain NETs (18.9 vs 4.4; P<.001). On a receiver operating characteristic curve analysis, a TBR of 2.5 had a sensitivity of 90% and a specificity of 25%, and a TBR of 16 had a sensitivity of 54% and a specificity of 81%.Conclusions and Relevance: A TBR of 2.5 or greater is a highly sensitive threshold for indicating a lesion to be consistent with a NET on histologic findings and thus warranting surgical resection. The omentum should be used as the background count activity for 68Ga-dotatate RGS for patients with abdominal NETs.
View details for PubMedID 30267071
Aggressive resection of neuroendocrine tumor (NET) liver metastases: NET neutral or gain?
View details for PubMedID 30266442
Predictors of Survival in Adrenocortical Carcinoma: An Analysis From the National Cancer Database
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
2018; 103 (9): 3566–73
Adrenocortical Carcinoma (ACC) is rare and knowledge on the prognostic factors and survival outcomes is limited.To describe predictors of survival and overall survival (OS) outcomes of ACC.Retrospective review of ACC patients from National Cancer Database (NCDB).Nationwide cancer registry based study.Pathologically confirmed 3185 ACC patients identified from NCDB between 2004 and 2015.Baseline description, survival outcomes, and predictors of survival were evaluated in patients with ACC.Median age at diagnosis of ACC was 55 (range:18-90) years and did not differ by sex or stage of disease at diagnosis. On multivariate analysis, increasing age (p < 0.0001), higher Charlson comorbidity index (p < 0.0001), high tumor grade (p < 0.0001), stage IV disease (p=0.002), no surgical therapy (p < 0.0001), and performance of lymphadenectomy during surgery (p=0.02) were associated with poor prognosis. In stage I-III disease, patients treated with surgical resection had significantly better median OS (63 vs 8 months, p <0.001). In stage IV disease, patients treated with surgery (19 vs 6 months, p < 0.001), and post-surgical radiation (29 vs 10 months, p < 0.001) or chemotherapy (22 vs 13 months, p=0.004) had a better median OS.OS of ACC varied with increasing age, higher comorbidity index, grade and stage of the disease at presentation. In addition, we noted improved survival with surgical resection of primary tumor, irrespective of the stage of the disease though, post-surgical chemo or radiation benefitted only in stage IV disease.
View details for PubMedID 29982685
Incidence and management of postoperative hyperglycemia in patients undergoing insulinoma resection
2018; 61 (3): 422–27
It has been proposed that rebound hyperglycemia after resection of insulinoma indicates a biochemical cure. However, there is scant objective data in the literature on the rate and need for intervention in hyperglycemia in patients undergoing resection of insulinoma. The goal of our study was to evaluate the rate of postoperative hyperglycemia, any predisposing factors, and the need for intervention in a prospective cohort study of all patients undergoing routine glucose monitoring.A retrospective analysis of 33 patients who had an insulinoma resected and who underwent routine postoperative monitoring of blood glucose (every hour for the first six hours then every four hours for the first 24 h) was performed. Hyperglycemia was defined as glucose greater than 180 mg/dL (10 mmol/l).Twelve patients (36%) developed hyperglycemia within 24 h (range 1-16 h). In patients with hyperglycemia, the mean maximum plasma glucose level was 221.5 mg/dL (range 97-325 mg/dL) (12.3 mmol/l), and four (33%) patients were treated with insulin. There was no significant difference in age, gender, body mass index (BMI), tumor size, biochemical profile, or surgical approach and extent of pancreatectomy between patients who developed hyperglycemia and those who did not. Pre-excision and post-excision intraoperative insulin levels were evaluated in 14 of 33 patients. The percentage decrease of the intraoperative insulin levels was not significantly different between patients who developed hyperglycemia and those who did not. All patients with postoperative hyperglycemia had normalization of their glucose levels, and none were discharged on anti-hyperglycemic agents.Hyperglycemia is common after insulinoma resection, and a subset of patients require transient treatment with insulin.
View details for PubMedID 29923016
- Neural monitoring in endocrine neck surgery GLAND SURGERY 2018; 7: S86–S88
Identification of Differential Transcriptional Patterns in Primary and Secondary Hyperparathyroidism
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
2018; 103 (6): 2189–98
Hyperparathyroidism is associated with hypercalcemia and the excess of parathyroid hormone secretion; however, the alterations in molecular pattern of functional genes during parathyroid tumorigenesis have not been unraveled. We aimed at establishing transcriptional patterns of normal and pathological parathyroid glands (PGs) in sporadic primary (HPT1) and secondary hyperparathyroidism (HPT2).To evaluate dynamic alterations in molecular patterns as a function of the type of PG pathology, a comparative transcript analysis was conducted in subgroups of healthy samples, sporadic HPT1 adenoma and hyperplasia, and HPT2.Normal, adenomatous, HPT1, and HPT2 hyperplastic PG formalin-fixed paraffin-embedded samples were subjected to NanoString analysis. In silico microRNA (miRNA) analyses and messenger RNA-miRNA network in PG pathologies were conducted. Individual messenger RNA and miRNA levels were assessed in snap-frozen PG samples.The expression levels of c-MET, MYC, TIMP1, and clock genes NFIL3 and PER1 were significantly altered in HPT1 adenoma compared with normal PG tissue when assessed by NanoString and quantitative reverse transcription polymerase chain reaction. RET was affected in HPT1 hyperplasia, whereas CaSR and VDR transcripts were downregulated in HPT2 hyperplastic PG tissue. CDH1, c-MET, MYC, and CaSR were altered in adenoma compared with hyperplasia. Correlation analyses suggest that c-MET, MYC, and NFIL3 exhibit collective expression level changes associated with HPT1 adenoma development. miRNAs, predicted in silico to target these genes, did not exhibit a clear tendency upon experimental validation.The presented gene expression analysis provides a differential molecular characterization of PG adenoma and hyperplasia pathologies, advancing our understanding of their etiology.
View details for PubMedID 29659895
The Immune Landscape of Cancer
2018; 48 (4): 812-+
We performed an extensive immunogenomic analysis of more than 10,000 tumors comprising 33 diverse cancer types by utilizing data compiled by TCGA. Across cancer types, we identified six immune subtypes-wound healing, IFN-γ dominant, inflammatory, lymphocyte depleted, immunologically quiet, and TGF-β dominant-characterized by differences in macrophage or lymphocyte signatures, Th1:Th2 cell ratio, extent of intratumoral heterogeneity, aneuploidy, extent of neoantigen load, overall cell proliferation, expression of immunomodulatory genes, and prognosis. Specific driver mutations correlated with lower (CTNNB1, NRAS, or IDH1) or higher (BRAF, TP53, or CASP8) leukocyte levels across all cancers. Multiple control modalities of the intracellular and extracellular networks (transcription, microRNAs, copy number, and epigenetic processes) were involved in tumor-immune cell interactions, both across and within immune subtypes. Our immunogenomics pipeline to characterize these heterogeneous tumors and the resulting data are intended to serve as a resource for future targeted studies to further advance the field.
View details for PubMedID 29628290
Comparative Molecular Analysis of Gastrointestinal Adenocarcinomas
2018; 33 (4): 721-+
We analyzed 921 adenocarcinomas of the esophagus, stomach, colon, and rectum to examine shared and distinguishing molecular characteristics of gastrointestinal tract adenocarcinomas (GIACs). Hypermutated tumors were distinct regardless of cancer type and comprised those enriched for insertions/deletions, representing microsatellite instability cases with epigenetic silencing of MLH1 in the context of CpG island methylator phenotype, plus tumors with elevated single-nucleotide variants associated with mutations in POLE. Tumors with chromosomal instability were diverse, with gastroesophageal adenocarcinomas harboring fragmented genomes associated with genomic doubling and distinct mutational signatures. We identified a group of tumors in the colon and rectum lacking hypermutation and aneuploidy termed genome stable and enriched in DNA hypermethylation and mutations in KRAS, SOX9, and PCBP1.
View details for PubMedID 29622466
Machine Learning Identifies Stemness Features Associated with Oncogenic Dedifferentiation
2018; 173 (2): 338-+
Cancer progression involves the gradual loss of a differentiated phenotype and acquisition of progenitor and stem-cell-like features. Here, we provide novel stemness indices for assessing the degree of oncogenic dedifferentiation. We used an innovative one-class logistic regression (OCLR) machine-learning algorithm to extract transcriptomic and epigenetic feature sets derived from non-transformed pluripotent stem cells and their differentiated progeny. Using OCLR, we were able to identify previously undiscovered biological mechanisms associated with the dedifferentiated oncogenic state. Analyses of the tumor microenvironment revealed unanticipated correlation of cancer stemness with immune checkpoint expression and infiltrating immune cells. We found that the dedifferentiated oncogenic phenotype was generally most prominent in metastatic tumors. Application of our stemness indices to single-cell data revealed patterns of intra-tumor molecular heterogeneity. Finally, the indices allowed for the identification of novel targets and possible targeted therapies aimed at tumor differentiation.
View details for PubMedID 29625051
Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas
2018; 23 (1): 194-+
This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smoking and/or human papillomavirus (HPV). SCCs harbor 3q, 5p, and other recurrent chromosomal copy-number alterations (CNAs), DNA mutations, and/or aberrant methylation of genes and microRNAs, which are correlated with the expression of multi-gene programs linked to squamous cell stemness, epithelial-to-mesenchymal differentiation, growth, genomic integrity, oxidative damage, death, and inflammation. Low-CNA SCCs tended to be HPV(+) and display hypermethylation with repression of TET1 demethylase and FANCF, previously linked to predisposition to SCC, or harbor mutations affecting CASP8, RAS-MAPK pathways, chromatin modifiers, and immunoregulatory molecules. We uncovered hypomethylation of the alternative promoter that drives expression of the ΔNp63 oncogene and embedded miR944. Co-expression of immune checkpoint, T-regulatory, and Myeloid suppressor cells signatures may explain reduced efficacy of immune therapy. These findings support possibilities for molecular classification and therapeutic approaches.
View details for PubMedID 29617660