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151. Integrative and Comparative Genomic Analysis of Lung Squamous Cell Carcinomas in East Asian Patients

Author: Young-Wook Kim, Andrey Sivachenko, Hong Kwan Kim, Gad Getz, Yeong Kyung Yoo, Jhingook Kim, Yoon-La Choi, Kyu Sik Kim, Yong Soo Choi, Jong Mu Sun, Michael S. Lawrence, Scott L. Carter, Keunchil Park, Chip Stewart, Matthew D. Wilkerson, Young Mog Shim, Petar Stojanov, Matthew Meyerson, Yoomi Lee, Kwhanmien Kim, Jin Seok Ahn, Sukki Cho, Jaegil Kim, D. Neil Hayes, Young-Chul Kim, Aaron McKenna, Sang Yun Song, Ji Ae Yoon, Myung-Ju Ahn, Kook Joo Na, Chandra Sekhar Pedamallu, Peter S. Hammerman, In-Jae Oh, and Kristian Cibulskis
Subjects: Male, Oncology, Cancer Research, Pathology, Lung Neoplasms, Somatic cell, Retinoblastoma Protein, Transcriptome, Phosphatidylinositol 3-Kinases, Aged, 80 and over, Kelch-Like ECH-Associated Protein 1, biology, Smoking, Intracellular Signaling Peptides and Proteins, ORIGINAL REPORTS, respiratory system, Middle Aged, Neoplasm Proteins, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, medicine.anatomical_structure, Carcinoma, Squamous Cell, Adenocarcinoma, Female, Adult, medicine.medical_specialty, Class I Phosphatidylinositol 3-Kinases, NF-E2-Related Factor 2, White People, Asian People, Internal medicine, Republic of Korea, medicine, Carcinoma, Humans, PTEN, Lung cancer, Aged, Lung, Models, Genetic, business.industry, PTEN Phosphohydrolase, Cancer, medicine.disease, United States, respiratory tract diseases, stomatognathic diseases, Mutation, biology.protein, Tumor Suppressor Protein p53, business
Abstract: Purpose Lung squamous cell carcinoma (SCC) is the second most prevalent type of lung cancer. Currently, no targeted therapeutics are approved for treatment of this cancer, largely because of a lack of systematic understanding of the molecular pathogenesis of the disease. To identify therapeutic targets and perform comparative analyses of lung SCC, we probed somatic genome alterations of lung SCC by using samples from Korean patients. Patients and Methods We performed whole-exome sequencing of DNA from 104 lung SCC samples from Korean patients and matched normal DNA. In addition, copy-number analysis and transcriptome analysis were conducted for a subset of these samples. Clinical association with cancer-specific somatic alterations was investigated. Results This cancer cohort is characterized by a high mutational burden with an average of 261 somatic exonic mutations per tumor and a mutational spectrum showing a signature of exposure to cigarette smoke. Seven genes demonstrated statistical enrichment for mutation: TP53, RB1, PTEN, NFE2L2, KEAP1, MLL2, and PIK3CA). Comparative analysis between Korean and North American lung SCC samples demonstrated a similar spectrum of alterations in these two populations in contrast to the differences seen in lung adenocarcinoma. We also uncovered recurrent occurrence of therapeutically actionable FGFR3-TACC3 fusion in lung SCC. Conclusion These findings provide new steps toward the identification of genomic target candidates for precision medicine in lung SCC, a disease with significant unmet medical needs.
Published: 2014
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152. Activation of the PD-1 Pathway Contributes to Immune Escape in EGFR-Driven Lung Tumors

Author: Glenn Dranoff, Gordon J. Freeman, Margaret Soucheray, Camilla L. Christensen, Matthew D. Wilkerson, Mohit Butaney, Lynette M. Sholl, Andrew D. Cherniack, Esra A. Akbay, D. Neil Hayes, Travis J. Cohoon, Kwok-Kin Wong, Shohei Koyama, Julian Carretero, Oliver Mikse, Peter S. Hammerman, Scott J. Rodig, Jeremy H. Tchaicha, Peter E. Fecci, Jacob B. Reibel, Pasi A. Jänne, Geoffrey I. Shapiro, Matthew Meyerson, Ellen M. Beauchamp, Abigail Altabef, Takeshi Shimamura, and Trevor J. Pugh
Subjects: Lung Neoplasms, T-Lymphocytes, T cell, Programmed Cell Death 1 Receptor, Mice, Transgenic, Lymphocyte Activation, B7-H1 Antigen, Article, Cell Line, Proinflammatory cytokine, Mice, Carcinoma, Non-Small-Cell Lung, Tumor Microenvironment, medicine, Animals, Humans, Cytotoxic T cell, Epidermal growth factor receptor, Lung cancer, EGFR inhibitors, Tumor microenvironment, biology, Oncogenes, medicine.disease, ErbB Receptors, Gene Expression Regulation, Neoplastic, Mice, Inbred C57BL, medicine.anatomical_structure, Oncology, Tumor Escape, Immunology, Cancer research, biology.protein, Cytokines, Signal Transduction
Abstract: The success in lung cancer therapy with programmed death (PD)-1 blockade suggests that immune escape mechanisms contribute to lung tumor pathogenesis. We identified a correlation between EGF receptor (EGFR) pathway activation and a signature of immunosuppression manifested by upregulation of PD-1, PD-L1, CTL antigen-4 (CTLA-4), and multiple tumor-promoting inflammatory cytokines. We observed decreased CTLs and increased markers of T-cell exhaustion in mouse models of EGFR-driven lung cancer. PD-1 antibody blockade improved the survival of mice with EGFR-driven adenocarcinomas by enhancing effector T-cell function and lowering the levels of tumor-promoting cytokines. Expression of mutant EGFR in bronchial epithelial cells induced PD-L1, and PD-L1 expression was reduced by EGFR inhibitors in non–small cell lung cancer cell lines with activated EGFR. These data suggest that oncogenic EGFR signaling remodels the tumor microenvironment to trigger immune escape and mechanistically link treatment response to PD-1 inhibition. Significance: We show that autochthonous EGFR-driven lung tumors inhibit antitumor immunity by activating the PD-1/PD-L1 pathway to suppress T-cell function and increase levels of proinflammatory cytokines. These findings indicate that EGFR functions as an oncogene through non–cell-autonomous mechanisms and raise the possibility that other oncogenes may drive immune escape. Cancer Discov; 3(12); 1355–63. ©2013 AACR. See related commentary by Rech and Vonderheide, p. 1330 This article is highlighted in the In This Issue feature, p. 1317
Published: 2013
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153. Gene-expression data integration to squamous cell lung cancer subtypes reveals drug sensitivity

Author: J S Liu, Di Wu, David Wang, Matthew D. Wilkerson, Y Pang, and Peter S. Hammerman
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Lung Neoplasms, Gene Expression, Antineoplastic Agents, Cell Growth Processes, Biology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Cell Line, Tumor, Internal medicine, Panobinostat, squamous cell lung cancer subtypes, medicine, Carcinoma, Humans, RNA, Neoplasm, drug sensitivity, Lung cancer, Molecular Diagnostics, 030304 developmental biology, signature genes, 0303 health sciences, Lung, Computational Biology, Cancer, RNAseq, medicine.disease, cells of origin, 3. Good health, representative cell line, Irinotecan, medicine.anatomical_structure, classification, chemistry, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Carcinoma, Squamous Cell, Adenocarcinoma, Topotecan, microarray, medicine.drug
Abstract: Background: Squamous cell lung cancer (SqCC) is the second most common type of lung cancer in the United States. Previous studies have used gene-expression data to classify SqCC samples into four subtypes, including the primitive, classical, secretory and basal subtypes. These subtypes have different survival outcomes, although it is unknown whether these molecular subtypes predict response to therapy. Methods: Here, we analysed RNAseq data of 178 SqCC tumour samples and characterised the features of the different SqCC subtypes to define signature genes and pathway alterations specific to each subtype. Further, we compared the gene-expression features of each molecular subtype to specific time points in models of airway development. We also classified SqCC-derived cell lines and their reported therapeutic vulnerabilities. Results: We found that the primitive subtype may come from a later stage of differentiation, whereas the basal subtype may be from an early time. Most SqCC cell lines responded to one of five anticancer drugs (Panobinostat, 17-AAG, Irinotecan, Topotecan and Paclitaxel), whereas the basal-type cell line EBC-1 was sensitive to three other drugs (PF2341066, AZD6244 and PD-0325901). Conclusion: Compared with the other three subtypes of cell lines, the secretory-type cell lines were significantly less sensitive to the five most effective drugs, possibly because of their low proliferation activity. We provide a bioinformatics framework to explore drug repurposing for cancer subtypes based on the available genomic profiles of tumour samples, normal cell types, cancer cell lines and data of drug sensitivity in cell lines. Lung cancer now accounts for 13% of new cancer cases and 29% of all cancer deaths each year in the United States. Lung cancer is the leading cause of cancer-related mortality worldwide, leading to an estimated 1.4 million deaths in 2010. Lung cancer is a heterogeneous disease with multiple histological and molecular subtypes. Lung cancers are usually classified according to the histological types because the histopathological type of lung cancer correlates with tumour behaviour and prognosis (Beadsmoore and Screaton, 2003). The vast majority of lung cancer types are carcinoma malignancies that arise from epithelial cells. The two most common subtypes of lung cancer are adenocarcinoma and squamous cell lung cancer types (SqCC). Squamous cell lung cancer is the second most common type of lung cancer, usually originating in the large airways in the central part of the lungs. Even for patients with SqCCs, outcomes are variable, suggesting that heterogeneity exists within this subtype. Further classification of SqCC into subtypes may help to understand the disease mechanism better, define the pathways relevant in disease origin and pathogenesis, and help guide treatment.
Published: 2013
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154. Prediction of Lung Cancer Histological Types by RT-qPCR Gene Expression in FFPE Specimens

Author: Michael Mullins, Charles M. Perou, Kenneth L. Muldrew, William K. Funkhouser, Xiaoying Yin, Katherine B. Geiersbach, Patrick J. Roberts, Jason M. Schallheim, D. Neil Hayes, Steven Bayer, Cheng Fan, Philip S. Bernard, Matthew D. Wilkerson, Roy R. L. Bastien, C. Ryan Miller, Leigh B. Thorne, and Michele C. Hayward
Subjects: Pathology, medicine.medical_specialty, Lung Neoplasms, Tissue Fixation, Biology, Bioinformatics, Small-cell carcinoma, Pathology and Forensic Medicine, 03 medical and health sciences, 0302 clinical medicine, Carcinoma, Non-Small-Cell Lung, Gene expression, Carcinoma, medicine, Humans, Lung cancer, 030304 developmental biology, Regulation of gene expression, 0303 health sciences, Paraffin Embedding, Reverse Transcriptase Polymerase Chain Reaction, Regular Article, Histology, medicine.disease, 3. Good health, Gene Expression Regulation, Neoplastic, Molecular Diagnostic Techniques, 030220 oncology & carcinogenesis, Adenocarcinoma, Molecular Medicine, DNA microarray
Abstract: Lung cancer histologic diagnosis is clinically relevant because there are histology-specific treatment indications and contraindications. Histologic diagnosis can be challenging owing to tumor characteristics, and it has been shown to have less-than-ideal agreement among pathologists reviewing the same specimens. Microarray profiling studies using frozen specimens have shown that histologies exhibit different gene expression trends; however, frozen specimens are not amenable to routine clinical application. Herein, we developed a gene expression–based predictor of lung cancer histology for FFPE specimens, which are routinely available in clinical settings. Genes predictive of lung cancer histologies were derived from published cohorts that had been profiled by microarrays. Expression of these genes was measured by quantitative RT-PCR (RT-qPCR) in a cohort of patients with FFPE lung cancer. A histology expression predictor (HEP) was developed using RT-qPCR expression data for adenocarcinoma, carcinoid, small cell carcinoma, and squamous cell carcinoma. In cross-validation, the HEP exhibited mean accuracy of 84% and κ = 0.77. In separate independent validation sets, the HEP was compared with pathologist diagnoses on the same tumor block specimens, and the HEP yielded similar accuracy and precision as the pathologists. The HEP also exhibited good performance in specimens with low tumor cellularity. Therefore, RT-qPCR gene expression from FFPE specimens can be effectively used to predict lung cancer histology.
Published: 2013
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155. Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma

Author: James Powers, Antonio M. Lerario, Sylvia L. Asa, Joel S. Parker, Erin Curley, D. Neil Hayes, Martin L. Ferguson, Tobias Else, Michael S. Noble, Liming Yang, Mark Gerken, Ina Felau, Donghui Tan, Doug Voet, Charis Eng, Tracy S. Wang, Erik Zmuda, Kiley Graim, Anouk van Berkel, Noreen Dhalla, Gad Getz, Nicole Maison, Alan P. Hoyle, Vlado Uzunangelov, Artem Sokolov, Virginia A. LiVolsi, Tomáš Zelinka, Evan Paul, Juliann Shih, David Haussler, Charles M. Perou, David Dimmock, Patrick K. Kimes, Rashi Naresh, Yiling Lu, Nina Thiessen, Manaswi Gupta, Fiemu E. Nwariaku, Scott Morris, John N. Weinstein, Brandon Wenz, Yair Lotan, Carrie Sougnez, Theo A. Knijnenburg, Angela Tam, Nilsa C. Ramirez, Candace Shelton, Richard A. Moore, Esther Korpershoek, Amy H. Perou, Ozgur Mete, Steven E. Schumacher, David I. Heiman, Eric Baudin, Tom Bodenheimer, Jia Liu, Lauren Fishbein, Troy Shelton, Jens Waldmann, Michael S. Lawrence, Jacqueline E. Schein, Robert Penny, Andrew D. Cherniack, Kane Tse, Harindra Arachchi, A. Gordon Robertson, Corbin D. Jones, Heidi J. Sofia, Stefanie Hahner, Carolyn M. Hutter, Rameen Beroukhim, Allison Beaver, Vonn Walter, JoEllen Weaver, Electron Kebebew, Sam Ng, Daniel Crain, Jennifer L. Rabaglia, Adrian Ally, Lynda Chin, Constanze Hantel, Matthew Meyerson, Mary Goldman, J. Todd Auman, Timo Deutschbein, John A. Demchok, Stacey B. Gabriel, Julie M. Gastier-Foster, Tina Wong, W. Kimryn Rathmell, Piotr A. Mieczkowski, Jiashan Zhang, Jaegil Kim, George E. Sandusky, David Haan, Franck Zinzindohoué, Josh Stuart, Antonio L. Amelio, Marco A. Marra, Todd Pihl, Felix Beuschlein, Roy Tarnuzzer, Tara Skelly, Andrew J. Mungall, Silviu Sbiera, Robert A. Holt, Katherine L. Nathanson, Charlie Sun, Ales Vicha, Tara M. Lichtenberg, Thomas Matthew, Sudha Chudamani, Sara Sadeghi, Laurence Amar, Suzie Carter, Jeffrey Roach, Laxmi Lolla, Kristen M. Leraas, Hans K. Ghayee, Michael Mayo, Ronald R. de Krijger, Lisle E. Mose, Payal Sipahimalani, Juok Cho, Eric Chuah, Bradley A. Murray, Johanna Gardner, Matthew D. Wilkerson, Massimo Mannelli, Nils Gehlenborg, Jessica Marquard, Anna Riester, Katherine Tarvin, Teresa Swatloski, Sofie R. Salama, Ignaty Leshchiner, Lisa Wise, Jingchun Zhu, Ludmila Danilova, Michael Feldman, Jean C. Zenklusen, Richard J. Auchus, Detlef K. Bartsch, Katherine A. Hoadley, Ian T. Fiddes, Matthew G. Soloway, Yussanne Ma, Henri J. Timmers, Tchao Meatchi, Eric Lander, Leslie Cope, Rehan Akbani, Aguirre A. de Cubas, Robert Baertsch, Amy R. Johnson, Winand N.M. Dinjens, Denise Brooks, Maria J. Merino, Steven J.M. Jones, Umadevi Veluvolu, Rebecca Carlsen, Katayoon Kasaian, Wei Zhang, Thomas J. Giordano, Ying Ni, Shaowu Meng, Mei Huang, Miruna Balasundaram, Ronald Lechan, Ilya Shmulevich, Reanne Bowlby, Dirk Weismann, Gordon Saksena, Karel Pacak, Jennifer Eschbacher, Margi Sheth, Shiyun Ling, Yan Shi, Clarissa A. Cassol, Anne Paule Gimenez-Roqueplo, Charles Saller, Darlene Lee, Ye Wu, Bryan Hunt, Arthur S. Tischler, David Mallery, Amie Radenbaugh, Christopher K. Wong, Pei Lin, Yulia Newton, Zhining Wang, Scott Frazer, Martin Fassnacht, Liza Makowski, Janae V. Simons, Jennifer Geurts, Gordon B. Mills, Arjun Rao, Leigh B. Thorne, Christopher C. Benz, Stuart R. Jefferys, Yunhu Wan, Olena Morozova, Thomas L. Bauer, Jay Bowen, Lori Boice, Saianand Balu, Pathology, Broad Institute of MIT and Harvard, Massachusetts Institute of Technology. Department of Biology, Massachusetts Institute of Technology. Department of Chemical Engineering, Leshchiner, Ignaty, and Lander, Eric Steven
Subjects: 0301 basic medicine, Male, Cancer Research, medicine.disease_cause, Fusion gene, paraganglioma, 0302 clinical medicine, Paraganglioma, Genetics, Aged, 80 and over, Mutation, Nuclear Proteins, RNA-Binding Proteins, sequencing, Middle Aged, pheochromocytoma, DNA-Binding Proteins, CSDE1, Proto-Oncogene Proteins c-ret, Oncology, 030220 oncology & carcinogenesis, Female, Gene Fusion, Pol1 Transcription Initiation Complex Proteins, MAML3, Adult, molecular profiling, Biology, Article, Pheochromocytoma, 03 medical and health sciences, Germline mutation, medicine, genomics, Journal Article, Humans, metastasis, HRAS, Gene, Aged, Cell Biology, TCGA, medicine.disease, expression subtypes, 030104 developmental biology, Cancer research, Trans-Activators, bacteria, Transcription Factors
Abstract: We report a comprehensive molecular characterization of pheochromocytomas and paragangliomas (PCCs/PGLs), a rare tumor type. Multi-platform integration revealed that PCCs/PGLs are driven by diverse alterations affecting multiple genes and pathways. Pathogenic germline mutations occurred in eight PCC/PGL susceptibility genes. We identified CSDE1 as a somatically mutated driver gene, complementing four known drivers (HRAS, RET, EPAS1, and NF1). We also discovered fusion genes in PCCs/PGLs, involving MAML3, BRAF, NGFR, and NF1. Integrated analysis classified PCCs/PGLs into four molecularly defined groups: a kinase signaling subtype, a pseudohypoxia subtype, a Wnt-altered subtype, driven by MAML3 and CSDE1, and a cortical admixture subtype. Correlates of metastatic PCCs/PGLs included the MAML3 fusion gene. This integrated molecular characterization provides a comprehensive foundation for developing PCC/PGL precision medicine., National Institutes of Health (U.S.) (Grant U54HG003273), National Institutes of Health (U.S.) (Grant U54HG003067), National Institutes of Health (U.S.) (Grant U54HG003079), National Institutes of Health (U.S.) (Grant U24CA143799), National Institutes of Health (U.S.) (Grant U24CA143835), National Institutes of Health (U.S.) (Grant U24CA143840), National Institutes of Health (U.S.) (Grant U24CA143843), National Institutes of Health (U.S.) (Grant U24CA143845), National Institutes of Health (U.S.) (Grant U24CA143848), National Institutes of Health (U.S.) (Grant U24CA143858), National Institutes of Health (U.S.) (Grant U24CA143866), National Institutes of Health (U.S.) (Grant U24CA143867), National Institutes of Health (U.S.) (Grant U24CA143882), National Institutes of Health (U.S.) (Grant U24CA143883), National Institutes of Health (U.S.) (Grant U24CA144025), National Institutes of Health (U.S.) (Grant P30CA016672)
Published: 2017

156. 'Soldier's Heart': A Genetic Basis for Elevated Cardiovascular Disease Risk Associated with Post-traumatic Stress Disorder

Author: Meera Srivastava, Murray B. Stein, Joshua Starr, Chittari Shivakumar, Matthew D. Wilkerson, Harvey B. Pollard, Ofer Eidelman, Clifton L. Dalgard, David M. Jacobowitz, and Robert J. Ursano
Subjects: 0301 basic medicine, Candidate gene, medicine.medical_specialty, Disease, Bioinformatics, lcsh:RC321-571, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Glucocorticoid receptor, cardiovascular disease, Hypothesis and Theory, Type 2 diabetes mellitus, mental disorders, medicine, Psychiatry, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Molecular Biology, Gene, post traumatic stress disorder, Soldier's heart, Mechanism (biology), Traumatic stress, candidate gene, Type 2 Diabetes Mellitus, Exact test, 030104 developmental biology, candidate genes, Psychology, 030217 neurology & neurosurgery, Neuroscience
Abstract: “Soldier's Heart,” is an American Civil War term linking post-traumatic stress disorder (PTSD) with increased propensity for cardiovascular disease (CVD). We have hypothesized that there might be a quantifiable genetic basis for this linkage. To test this hypothesis we identified a comprehensive set of candidate risk genes for PTSD, and tested whether any were also independent risk genes for CVD. A functional analysis algorithm was used to identify associated signaling networks. We identified 106 PTSD studies that report one or more polymorphic variants in 87 candidate genes in 83,463 subjects and controls. The top upstream drivers for these PTSD risk genes are predicted to be the glucocorticoid receptor (NR3C1) and Tumor Necrosis Factor alpha (TNFA). We find that 37 of the PTSD candidate risk genes are also candidate independent risk genes for CVD. The association between PTSD and CVD is significant by Fisher's Exact Test (P = 3 × 10−54). We also find 15 PTSD risk genes that are independently associated with Type 2 Diabetes Mellitus (T2DM; also significant by Fisher's Exact Test (P = 1.8 × 10−16). Our findings offer quantitative evidence for a genetic link between post-traumatic stress and cardiovascular disease, Computationally, the common mechanism for this linkage between PTSD and CVD is innate immunity and NFκB-mediated inflammation.
Published: 2016
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157. Integrated Molecular Characterization of Uterine Carcinosarcoma

Author: Andrew D. Cherniack, Hui Shen, Vonn Walter, Chip Stewart, Bradley A. Murray, Reanne Bowlby, Xin Hu, Shiyun Ling, Robert A. Soslow, Russell R. Broaddus, Rosemary E. Zuna, Gordon Robertson, Peter W. Laird, Raju Kucherlapati, Gordon B. Mills, John N. Weinstein, Jiashan Zhang, Rehan Akbani, Douglas A. Levine, Adrian Ally, J. Todd Auman, Miruna Balasundaram, Saianand Balu, Stephen B. Baylin, Rameen Beroukhim, Tom Bodenheimer, Faina Bogomolniy, Lori Boice, Moiz S. Bootwalla, Jay Bowen, Russell Broaddus, Denise Brooks, Rebecca Carlsen, Juok Cho, Eric Chuah, Sudha Chudamani, Kristian Cibulskis, Melissa Cline, Fanny Dao, Mutch David, John A. Demchok, Noreen Dhalla, Sean Dowdy, Ina Felau, Martin L. Ferguson, Scott Frazer, Jessica Frick, Stacey Gabriel, Julie M. Gastier-Foster, Nils Gehlenborg, Mark Gerken, Gad Getz, Manaswi Gupta, David Haussler, D. Neil Hayes, David I. Heiman, Julian Hess, Katherine A. Hoadley, Robert Hoffmann, Robert A. Holt, Alan P. Hoyle, Mei Huang, Carolyn M. Hutter, Stuart R. Jefferys, Steven J.M. Jones, Corbin D. Jones, Rupa S. Kanchi, Cyriac Kandoth, Katayoon Kasaian, Sarah Kerr, Jaegil Kim, Phillip H. Lai, Eric Lander, Michael S. Lawrence, Darlene Lee, Kristen M. Leraas, Ignaty Leshchiner, Tara M. Lichtenberg, Pei Lin, Jia Liu, Wenbin Liu, Yuexin Liu, Laxmi Lolla, Yiling Lu, Yussanne Ma, Dennis T. Maglinte, Marco A. Marra, Michael Mayo, Shaowu Meng, Matthew Meyerson, Piotr A. Mieczkowski, Richard A. Moore, Lisle E. Mose, Andrew J. Mungall, Karen Mungall, Rashi Naresh, Michael S. Noble, Narciso Olvera, Joel S. Parker, Charles M. Perou, Amy H. Perou, Todd Pihl, Amie J. Radenbaugh, Nilsa C. Ramirez, W. Kimryn Rathmell, Jeffrey Roach, A. Gordon Robertson, Sara Sadeghi, Gordon Saksena, Helga B. Salvesen, Jacqueline E. Schein, Steven E. Schumacher, Margi Sheth, Yan Shi, Juliann Shih, Janae V. Simons, Payal Sipahimalani, Tara Skelly, Heidi J. Sofia, Matthew G. Soloway, Carrie Sougnez, Charlie Sun, Angela Tam, Donghui Tan, Roy Tarnuzzer, Nina Thiessen, Leigh B. Thorne, Kane Tse, Jill Tseng, David J. Van Den Berg, Umadevi Veluvolu, Roel G.W. Verhaak, Doug Voet, Amanda von Bismarck, Yunhu Wan, Zhining Wang, Chen Wang, Daniel J. Weisenberger, Matthew D. Wilkerson, Boris Winterhoff, Lisa Wise, Tina Wong, Ye Wu, Liming Yang, Jean C. Zenklusen, Jiashan (Julia) Zhang, Hailei Zhang, Wei Zhang, Jing-chun Zhu, and Erik Zmuda
Subjects: 0301 basic medicine, Cancer Research, Epithelial-Mesenchymal Transition, DNA Copy Number Variations, medicine.disease_cause, Article, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Carcinosarcoma, medicine, PTEN, Humans, Epigenetics, Uterine Neoplasm, Epigenomics, biology, Gene signature, medicine.disease, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Mutation, Uterine Neoplasms, Cancer research, biology.protein, Female, KRAS
Abstract: We performed genomic, epigenomic, transcriptomic, and proteomic characterizations of uterine carcinosarcomas (UCSs). Cohort samples had extensive copy-number alterations and highly recurrent somatic mutations. Frequent mutations were found in TP53, PTEN, PIK3CA, PPP2R1A, FBXW7, and KRAS, similar to endometrioid and serous uterine carcinomas. Transcriptome sequencing identified a strong epithelial-to-mesenchymal transition (EMT) gene signature in a subset of cases that was attributable to epigenetic alterations at microRNA promoters. The range of EMT scores in UCS was the largest among all tumor types studied via The Cancer Genome Atlas. UCSs shared proteomic features with gynecologic carcinomas and sarcomas with intermediate EMT features. Multiple somatic mutations and copy-number alterations in genes that are therapeutic targets were identified.
Published: 2016

158. Cafeteria diet-induced obesity causes oxidative damage in white adipose

Author: Brante P. Sampey, Melissa A. Troester, Liza Makowski, Matthew D. Wilkerson, D. Neil Hayes, and Amy R. Johnson
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, Adipose Tissue, White, Biophysics, Adipose tissue, 030209 endocrinology & metabolism, White adipose tissue, medicine.disease_cause, Diet, High-Fat, Biochemistry, Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Diabetes mellitus, medicine, Hyperinsulinemia, Animals, Humans, Obesity, Rats, Wistar, Molecular Biology, Tissue homeostasis, Inflammation, biology, Cell Biology, medicine.disease, Glutathione, Diet, Insulin receptor, Oxidative Stress, 030104 developmental biology, Endocrinology, Gene Expression Regulation, biology.protein, medicine.symptom, Transcriptome, Weight gain, Oxidative stress
Abstract: Obesity continues to be one of the most prominent public health dilemmas in the world. The complex interaction among the varied causes of obesity makes it a particularly challenging problem to address. While typical high-fat purified diets successfully induce weight gain in rodents, we have described a more robust model of diet-induced obesity based on feeding rats a diet consisting of highly palatable, energy-dense human junk foods - the "cafeteria" diet (CAF, 45-53% kcal from fat). We previously reported that CAF-fed rats became hyperphagic, gained more weight, and developed more severe hyperinsulinemia, hyperglycemia, and glucose intolerance compared to the lard-based 45% kcal from fat high fat diet-fed group. In addition, the CAF diet-fed group displayed a higher degree of inflammation in adipose and liver, mitochondrial dysfunction, and an increased concentration of lipid-derived, pro-inflammatory mediators. Building upon our previous findings, we aimed to determine mechanisms that underlie physiologic findings in the CAF diet. We investigated the effect of CAF diet-induced obesity on adipose tissue specifically using expression arrays and immunohistochemistry. Genomic evidence indicated the CAF diet induced alterations in the white adipose gene transcriptome, with notable suppression of glutathione-related genes and pathways involved in mitigating oxidative stress. Immunohistochemical analysis indicated a doubling in adipose lipid peroxidation marker 4-HNE levels compared to rats that remained lean on control standard chow diet. Our data indicates that the CAF diet drives an increase in oxidative damage in white adipose tissue that may affect tissue homeostasis. Oxidative stress drives activation of inflammatory kinases that can perturb insulin signaling leading to glucose intolerance and diabetes.
Published: 2016

159. A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response

Author: Diego H. Castrillon, Michael D. Cameron, Carrie B. Lee, Tanya Tupper, Nabeel Bardeesy, Hiromichi Ebi, Chunxiao Xu, Mizuki Nishino, Yuchuan Wang, Christopher G. Peña, Patrick J. Roberts, Yanping Sun, Mohit Butaney, Jing Ouyang, Pasi A. Jänne, Jeffrey A. Engelman, Charles Lee, George D. Demetri, Jie Li, Lewis C. Cantley, Zhao Chen, Takeshi Shimamura, Shumei Wang, David M. Jackman, Katherine A. Cheng, Kwok-Kin Wong, Norman E. Sharpless, Amy Saur, Catherine Yao, Abigail Altabef, Michele S. Woo, D. Neil Hayes, Masahiko Yanagita, Yuji Nakada, Matthew D. Wilkerson, Andrew L. Kung, Pier Paolo Pandolfi, Lucian R. Chirieac, Peng Gao, Zandra E. Walton, Yoko Franchetti, Daniel B. Costa, and Yan Liu
Subjects: Oncology, medicine.medical_specialty, Lung Neoplasms, MAP Kinase Signaling System, medicine.medical_treatment, Drug Evaluation, Preclinical, Docetaxel, AMP-Activated Protein Kinases, Protein Serine-Threonine Kinases, medicine.disease_cause, Article, Targeted therapy, Proto-Oncogene Proteins p21(ras), Mice, Clinical Trials, Phase II as Topic, Fluorodeoxyglucose F18, Proto-Oncogene Proteins, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, medicine, Animals, Humans, Lung cancer, Randomized Controlled Trials as Topic, Mitogen-Activated Protein Kinase Kinases, Multidisciplinary, business.industry, MEK inhibitor, Reproducibility of Results, Cancer, Genes, p53, medicine.disease, Clinical trial, Disease Models, Animal, Treatment Outcome, Pharmacogenetics, Positron-Emission Tomography, Mutation, Immunology, ras Proteins, Selumetinib, Benzimidazoles, Taxoids, KRAS, Tomography, X-Ray Computed, business, medicine.drug
Abstract: Targeted therapies have demonstrated efficacy against specific subsets of molecularly defined cancers1–4. Although most patients with lung cancer are stratified according to a single oncogenic driver, cancers harbouring identical activating genetic mutations show large variations in their responses to the same targeted therapy1,3. The biology underlying this heterogeneity is not well understood, and the impact of co-existing genetic mutations, especially the loss of tumour suppressors5–9, has not been fully explored. Here we use genetically engineered mouse models to conduct a ‘co-clinical’ trial that mirrors an ongoing human clinical trial in patients with KRAS-mutant lung cancers. This trial aims to determine if the MEK inhibitor selumetinib (AZD6244)10 increases the efficacy of docetaxel, a standard of care chemotherapy. Our studies demonstrate that concomitant loss of either p53 (also known as Tp53) or Lkb1 (also known as Stk11), two clinically relevant tumour suppressors6,9,11,12, markedly impaired the response of Kras-mutant cancers to docetaxel monotherapy. We observed that the addition of selumetinib provided substantial benefit for mice with lung cancer caused by Kras and Kras and p53 mutations, but mice with Kras and Lkb1 mutations had primary resistance to this combination therapy. Pharmacodynamic studies, including positron-emission tomography (PET) and computed tomography (CT), identified biological markers in mice and patients that provide a rationale for the differential efficacy of these therapies in the different genotypes. These co-clinical results identify predictive genetic biomarkers that should be validated by interrogating samples from patients enrolled on the concurrent clinical trial. These studies also highlight the rationale for synchronous co-clinical trials, not only to anticipate the results of ongoing human clinical trials, but also to generate clinically relevant hypotheses that can inform the analysis and design of human studies.
Published: 2012
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160. Lung Squamous Cell Carcinoma mRNA Expression Subtypes Are Reproducible, Clinically Important, and Correspond to Normal Cell Types

Author: C. Ryan Miller, D. Neil Hayes, Yufeng Liu, Michele C. Hayward, Charles M. Perou, Carrie B. Lee, Alden M. Parsons, Philip S. Bernard, Kenneth L. Muldrew, Scott H. Randell, Katherine A. Hoadley, Matthew D. Wilkerson, Leigh B. Thorne, Patrick J. Roberts, Mark A. Socinski, Xiaoying Yin, Christopher R. Cabanski, and William K. Funkhouser
Subjects: Male, Oncology, Cancer Research, medicine.medical_specialty, Cell type, Pathology, Lung Neoplasms, Cell, Biology, Article, Cohort Studies, Basal (phylogenetics), Internal medicine, Carcinoma, medicine, Humans, RNA, Messenger, Survival analysis, Aged, Oligonucleotide Array Sequence Analysis, Genetic heterogeneity, Reproducibility of Results, Cancer, Middle Aged, medicine.disease, Survival Analysis, Gene Expression Regulation, Neoplastic, stomatognathic diseases, Treatment Outcome, medicine.anatomical_structure, Carcinoma, Squamous Cell, Female, DNA microarray
Abstract: Purpose: Lung squamous cell carcinoma (SCC) is clinically and genetically heterogeneous, and current diagnostic practices do not adequately substratify this heterogeneity. A robust, biologically based SCC subclassification may describe this variability and lead to more precise patient prognosis and management. We sought to determine if SCC mRNA expression subtypes exist, are reproducible across multiple patient cohorts, and are clinically relevant. Experimental Design: Subtypes were detected by unsupervised consensus clustering in five published discovery cohorts of mRNA microarrays, totaling 382 SCC patients. An independent validation cohort of 56 SCC patients was collected and assayed by microarrays. A nearest-centroid subtype predictor was built using discovery cohorts. Validation cohort subtypes were predicted and evaluated for confirmation. Subtype survival outcome, clinical covariates, and biological processes were compared by statistical and bioinformatic methods. Results: Four lung SCC mRNA expression subtypes, named primitive, classical, secretory, and basal, were detected and independently validated (P < 0.001). The primitive subtype had the worst survival outcome (P < 0.05) and is an independent predictor of survival (P < 0.05). Tumor differentiation and patient sex were associated with subtype. The expression profiles of the subtypes contained distinct biological processes (primitive: proliferation; classical: xenobiotic metabolism; secretory: immune response; basal: cell adhesion) and suggested distinct pharmacologic interventions. Comparison with lung model systems revealed distinct subtype to cell type correspondence. Conclusions: Lung SCC consists of four mRNA expression subtypes that have different survival outcomes, patient populations, and biological processes. The subtypes stratify patients for more precise prognosis and targeted research. Clin Cancer Res; 16(19); 4864–75. ©2010 AACR.
Published: 2010
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161. Abstract 5352: Racial/ethnic differences in prostate cancer genomic alterations

Author: Gyorgy Petrovics, Jun Hou, Yixue Li, Zoltan Szallasi, Jesse M. Fox, Heng-Cheng Hu, Shiv Srivastava, Clifton L. Dalgard, Yongmei Chen, Yingjie Song, Joel T. Moncur, Cara Schafer, Jacob Kagan, Guo-Ping Zhao, Wendy Wang, Sudhir Srivastava, Isabell A. Sesterhenn, Inger L. Rosner, Qingyu Xiao, Reinhard Ebner, Matthew D. Wilkerson, Joseph C. Cheng, Yuan Ji, Hua Li, Matthew L. Freedman, Gauthaman Sukumar, Shyh-Han Tan, Yidi Sun, Kevin Babcock, Albert Dobi, Jennifer Cullen, Denise Young, and Lakshmi Ravindranath
Subjects: Oncology, Cancer Research, medicine.medical_specialty, biology, business.industry, Cancer, medicine.disease, genomic DNA, Prostate cancer, Internal medicine, PARP inhibitor, medicine, biology.protein, SNP, PTEN, Racial/ethnic difference, business, Erg
Abstract: Background: Distinct biology of prostate cancer (CaP) among men of different races and ethnicities have been recently highlighted. Along these lines higher frequencies of the most common CaP gene alterations, ERG proto-oncogene activation and deletion of the PTEN tumor suppressor, have been reported among Caucasian Americans (CA) when compared to other racial/ethnic groups. We have reported the cumulative analyses of CaPs from 435 patients (whole genome sequencing (WGS), FISH evaluations and SNP arrays) that highlighted the recurrent deletion and disease progression association of the Limbic System-Associated Membrane Protein (LSAMP) in CaP genomes of African American (AA) men. Further examination of these data indicated the AA CaP genome associated recurrent deletion of the Chromodomain Helicase DNA Binding Protein 1(CHD1) gene. Methods: Combined evaluation of frequencies and prognostic associations of ERG oncoprotein by immunohistochemistry and deletions of LSAMP, CHD1 and PTEN genes by FISH were performed using a multi-core TMA (42 AA and 59 CA patients) with longitudinal follow up data (median 16 years). CaP and matched blood genomic DNA samples (N=60) from AA patients were analyzed by WGS. ERG frequencies were further evaluated in index tumors of Chinese CaPs (N=100) and were compared to ERG frequencies in index tumors of AA (N=336) and CA (N=594) patients. Results: Frequent deletions of CHD1 (29% AA vs. 10% CA p=0.017) and LSAMP (26% AA vs. 7% CA, p=0.006) were found in AA CaPs by FISH assay. Both of these deletions were associated with rapid disease progression. Evaluation of CaPs by WGS further highlighted the recurrent deletion of CHD1 among AA men. Comparative evaluation of ERG (AA, N=336; CA, N=594, and Asian N=100) underscored highest ERG frequencies among CA patients (49.3%) followed by AA (23.2%) and Chinese (22%) men. Conclusions: In light of distinct biology of CaPs in ethnically/racially diverse CaP patient populations there is a need for developing broadly applicable diagnostic, prognostic marker panels and therapeutic approaches. Recurrent CHD1 deletion in CaPs of AA patients may provide new therapeutic opportunities in light of recent reports suggesting that CaP patients harboring CHD1 deletion may benefit from PARP inhibitor or platinum agents therapies. Funding: This study was supported by CPDR, USUHS, HU0001-10-2-0002 to I.L.R., the NCI/EDRN IAA ACN12011-001-0 to S.S. and by the NCI R01CA162383 to S.S. Citation Format: Albert Dobi, Gyorgy Petrovics, Shyh-Han Tan, Hua Li, Denise Young, Cara Schafer, Jesse Fox, Kevin Babcock, Heng-Cheng Hu, Gauthaman Sukumar, Yingjie Song, Lakshmi Ravindranath, Yongmei Chen, Joseph Cheng, Reinhard Ebner, Qingyu Xiao, Yidi Sun, Yixue Li, Yuan Ji, Jun Hou, Wendy Wang, Guo-Ping Zhao, Jacob Kagan, Sudhir Srivastava, Joel T. Moncur, Clifton L. Dalgard, Matthew Wilkerson, Inger L. Rosner, Jennifer Cullen, Matthew Freedman, Zoltan Szallasi, Isabell A. Sesterhenn, Shiv Srivastava. Racial/ethnic differences in prostate cancer genomic alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5352.
Published: 2018
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162. Abstract 5354: Novel genomic alterations in renal medullary carcinoma tumors

Author: Inger L. Rosner, Jesse Fox, Clifton L. Dalgard, Matthew D. Wilkerson, Yingjie Song, Anthony R. Soltis, Denise Young, Shyh-Han Tan, Shiv Srivastava, Heng-Cheng Hu, and Isabell A. Sesterhenn
Subjects: Chromosome 7 (human), Cancer Research, Cancer, Biology, medicine.disease, Fusion gene, Renal medullary carcinoma, Chromosome 15, Oncology, medicine, Cancer research, Anaplastic lymphoma kinase, SMARCB1, Exome sequencing
Abstract: Introduction: Renal medullary carcinoma (RMC) is an rare but aggressive non-clear cell carcinoma that occurs predominantly in young African American (AA) men who carry the sickle cell trait. Our knowledge of the molecular basis for the initiation and progression of this cancer remains inadequate to establish standard of care treatments. As a result, even with surgery and chemotherapy, outcomes have remained dismal, with a median overall survival of approximately 13 months. Most patients with RMC exhibit deletion of the SMARCB1 gene, which encodes for a subunit of the SWI/SNF chromatin remodeling complex. Subtypes of RMC without SMARCB1 loss but harbor a rare gene fusion between Vinculin and Anaplastic Lymphoma Kinase have also been reported. We hypothesize that whole exome sequencing (WES) of RMC tumors will identify novel genomic alterations responsible for RMC tumor initiation and progression, which may provide actionable targets for treatment. Methods: Formalin fixed paraffin embedded (FFPE) RMC tumor and adjacent tissue specimens of 21 African American patients were obtained from the Joint Pathology Center. DNA were isolated from tumor and normal tissues with the Qiagen FFPE All Prep kit and measured by using the Qubit fluorometer. Integrity of the DNA samples were evaluated by using the Advanced Analytics Fragment Analyzer. WES DNA libraries were prepared from DNA samples that passed quality control using the Illumina TruSeq WES kit. Paired end sequencing (2x75) was performed on the Illumina HiSeq3000 platform. RMC tissues sections were analyzed for the expression of SMARCB1, VHL, HIF2A, AURKA, and EZH2 proteins by immunohistochemistry (IHC). Results: Somatic copy number alterations were estimated from the WES of seven RMC cases. These include recurrent large scale DNA alterations involving chromosome 7 and 8 amplification and chromosome 15 deletion. Focal DNA copy number alterations were also identified in the cohort, including deletion of SMARCB1. Analysis of somatic sequence mutations detected a canonical hotspot mutation (R132C) in IDH1 and recurrent non-silent mutations on RBM47 and NF2. Evaluation by IHC showed the loss of SMARCB1 expression in all cases assayed. Upregulation of EZH2 and AURKA, which are negatively regulated by SMARCB1, were detected in 3 of 21 and 11 of 21 cases, respectively. Focal HIF2A staining was detected in 7 of 21 tumor cases. Conclusions: The recurrent somatic sequence mutations, gene amplifications and deletions identified in this study reveal potential novel oncogenic drivers of RMC. Further validation of these genomic alterations may offer additional insight into the initiation and progression of RMC and provide actionable targets for establishing standard of care treatments. Source of Funding: The work is supported a grant award (HU0001-14-2-0041) to ST from the Collaborative Health Initiative Research Program (CHIRP), a precision medicine-based collaborative effort between the NIH and the DOD. Citation Format: Jesse Fox, Denise Young, Yingjie Song, Heng Cheng Hu, Anthony Soltis, Matthew D. Wilkerson, Clifton L. Dalgard, Inger L. Rosner, Isabell A. Sesterhenn, Shiv Srivastava, Shyh-Han Tan. Novel genomic alterations in renal medullary carcinoma tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5354.
Published: 2018
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163. Abstract 2281: Flexible discovery of recurrent coding and non-coding mutations in tumor whole genomes

Author: Harvey B. Pollard, Robert F. Browning, Craig D. Shriver, Anthony R. Soltis, Coralie Viollet, Christopher A. Moskaluk, Clifton L. Dalgard, and Matthew D. Wilkerson
Subjects: Cancer Research, Oncology, Computational biology, Biology, Genome, Coding (social sciences)
Abstract: Analysis of somatic protein-coding mutations, particularly via tumor exome sequencing, has driven discovery of novel cancer genes in recent years. However, ~97% of the human genome is non-coding and not addressable by exome-targeting methods. Tumor whole genome sequencing, by contrast, allows for genome-wide discovery of somatic events and may identify novel non-coding driver mutations. In conjunction, flexible tools employing principled statistical methods are needed for discovery of recurrent somatic driver mutations from tumor whole genomes. Here, we developed a computational toolset that addresses these needs and describe its application to a novel cohort of lung adenocarcinoma tumors generated by the APOLLO (Applied Proteogenomics OrganizationaL Learning and Outcomes) consortium. Our toolset flexibly computes feature-wise and hotspot somatic mutation enrichment statistics in both protein-coding and non-coding (e.g. promoters, enhancers) genomic regions. Additionally, we incorporated an affinity propagation-based clustering procedure that groups test regions by user-specified genomic covariates that can influence local mutation properties. We applied our toolset to several TCGA datasets of tumor exome sequencing. We found strong agreement between our results and those of other tools: among the top 15 genes called at FDR < 0.01 by MutSigCV, we observed a median overlap of 75.7% with genes ranked in the top 15 by our methods. We next applied our toolset to tumor whole genome sequencing data from our APOLLO lung adenocarcinoma cohort. During analysis, we simultaneously controlled for several genomic covariates, including GC/CpG content, replication timing, and proximal mRNA expression. Gene-centric analysis identified several significantly mutated genes, including KRAS, STK11, and TP53 (FDR < 0.005). We examined matched mRNA-seq data from this cohort and found significant over-expression of KRAS mRNA in samples possessing a non-silent coding mutation in this gene (p < 0.02). We additionally assessed somatic mutation enrichment in promoters, 3' UTRs, non-coding genes, and lung-specific enhancers. From these results, we found significant enrichment of somatic mutations in the body of the long non-coding RNA NEAT1. Among the tumors with somatic NEAT1 mutations, a single sample was hypermutated at this locus and corresponded with the lowest observed RNA expression for this lncRNA in our cohort (TPM of 12.2 vs. overall mean TPM of 84.2). In conclusion, we developed a flexible toolset for interrogating both coding and non-coding landscapes from tumor whole genomes. We applied our methods to a novel cohort of lung adenocarcinoma tumors and identified recurrently mutated genes and non-coding regions, including the NEAT1 lncRNA. Citation Format: Anthony R. Soltis, Coralie Viollet, Harvey B. Pollard, Christopher A. Moskaluk, Robert F. Browning, Clifton L. Dalgard, Craig D. Shriver, Matthew D. Wilkerson. Flexible discovery of recurrent coding and non-coding mutations in tumor whole genomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2281.
Published: 2018
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164. lncRNA Epigenetic Landscape Analysis Identifies EPIC1 as an Oncogenic lncRNA that Interacts with MYC and Promotes Cell-Cycle Progression in Cancer

Author: Zehua Wang, Bo Yang, Min Zhang, Weiwei Guo, Zhiyuan Wu, Yue Wang, Lin Jia, Song Li, Wen Xie, Da Yang, Samantha J. Caesar-Johnson, John A. Demchok, Ina Felau, Melpomeni Kasapi, Martin L. Ferguson, Carolyn M. Hutter, Heidi J. Sofia, Roy Tarnuzzer, Zhining Wang, Liming Yang, Jean C. Zenklusen, Jiashan (Julia) Zhang, Sudha Chudamani, Jia Liu, Laxmi Lolla, Rashi Naresh, Todd Pihl, Qiang Sun, Yunhu Wan, Ye Wu, Juok Cho, Timothy DeFreitas, Scott Frazer, Nils Gehlenborg, Gad Getz, David I. Heiman, Jaegil Kim, Michael S. Lawrence, Pei Lin, Sam Meier, Michael S. Noble, Gordon Saksena, Doug Voet, Hailei Zhang, Brady Bernard, Nyasha Chambwe, Varsha Dhankani, Theo Knijnenburg, Roger Kramer, Kalle Leinonen, Yuexin Liu, Michael Miller, Sheila Reynolds, Ilya Shmulevich, Vesteinn Thorsson, Wei Zhang, Rehan Akbani, Bradley M. Broom, Apurva M. Hegde, Zhenlin Ju, Rupa S. Kanchi, Anil Korkut, Jun Li, Han Liang, Shiyun Ling, Wenbin Liu, Yiling Lu, Gordon B. Mills, Kwok-Shing Ng, Arvind Rao, Michael Ryan, Jing Wang, John N. Weinstein, Jiexin Zhang, Adam Abeshouse, Joshua Armenia, Debyani Chakravarty, Walid K. Chatila, Inode Bruijn, Jianjiong Gao, Benjamin E. Gross, Zachary J. Heins, Ritika Kundra, Konnor La, Marc Ladanyi, Augustin Luna, Moriah G. Nissan, Angelica Ochoa, Sarah M. Phillips, Ed Reznik, Francisco Sanchez-Vega, Chris Sander, Nikolaus Schultz, Robert Sheridan, S. Onur Sumer, Yichao Sun, Barry S. Taylor, Jioajiao Wang, Hongxin Zhang, Pavana Anur, Myron Peto, Paul Spellman, Christopher Benz, Joshua M. Stuart, Christopher K. Wong, Christina Yau, D. Neil Hayes, Joel S. Parker, Matthew D. Wilkerson, Adrian Ally, Miruna Balasundaram, Reanne Bowlby, Denise Brooks, Rebecca Carlsen, Eric Chuah, Noreen Dhalla, Robert Holt, Steven J.M. Jones, Katayoon Kasaian, Darlene Lee, Yussanne Ma, Marco A. Marra, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Karen Mungall, A. Gordon Robertson, Sara Sadeghi, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Nina Thiessen, Kane Tse, Tina Wong, Ashton C. Berger, Rameen Beroukhim, Andrew D. Cherniack, Carrie Cibulskis, Stacey B. Gabriel, Galen F. Gao, Gavin Ha, Matthew Meyerson, Steven E. Schumacher, Juliann Shih, Melanie H. Kucherlapati, Raju S. Kucherlapati, Stephen Baylin, Leslie Cope, Ludmila Danilova, Moiz S. Bootwalla, Phillip H. Lai, Dennis T. Maglinte, David J. Van Den Berg, Daniel J. Weisenberger, J. Todd Auman, Saianand Balu, Tom Bodenheimer, Cheng Fan, Katherine A. Hoadley, Alan P. Hoyle, Stuart R. Jefferys, Corbin D. Jones, Shaowu Meng, Piotr A. Mieczkowski, Lisle E. Mose, Amy H. Perou, Charles M. Perou, Jeffrey Roach, Yan Shi, Janae V. Simons, Tara Skelly, Matthew G. Soloway, Donghui Tan, Umadevi Veluvolu, Huihui Fan, Toshinori Hinoue, Peter W. Laird, Hui Shen, Wanding Zhou, Michelle Bellair, Kyle Chang, Kyle Covington, Chad J. Creighton, Huyen Dinh, HarshaVardhan Doddapaneni, Lawrence A. Donehower, Jennifer Drummond, Richard A. Gibbs, Robert Glenn, Walker Hale, Yi Han, Jianhong Hu, Viktoriya Korchina, Sandra Lee, Lora Lewis, Wei Li, Xiuping Liu, Margaret Morgan, Donna Morton, Donna Muzny, Jireh Santibanez, Margi Sheth, Eve Shinbrot, Linghua Wang, Min Wang, David A. Wheeler, Liu Xi, Fengmei Zhao, Julian Hess, Elizabeth L. Appelbaum, Matthew Bailey, Matthew G. Cordes, Li Ding, Catrina C. Fronick, Lucinda A. Fulton, Robert S. Fulton, Cyriac Kandoth, Elaine R. Mardis, Michael D. McLellan, Christopher A. Miller, Heather K. Schmidt, Richard K. Wilson, Daniel Crain, Erin Curley, Johanna Gardner, Kevin Lau, David Mallery, Scott Morris, Joseph Paulauskis, Robert Penny, Candace Shelton, Troy Shelton, Mark Sherman, Eric Thompson, Peggy Yena, Jay Bowen, Julie M. Gastier-Foster, Mark Gerken, Kristen M. Leraas, Tara M. Lichtenberg, Nilsa C. Ramirez, Lisa Wise, Erik Zmuda, Niall Corcoran, Tony Costello, Christopher Hovens, Andre L. Carvalho, Ana C. de Carvalho, José H. Fregnani, Adhemar Longatto-Filho, Rui M. Reis, Cristovam Scapulatempo-Neto, Henrique C.S. Silveira, Daniel O. Vidal, Andrew Burnette, Jennifer Eschbacher, Beth Hermes, Ardene Noss, Rosy Singh, Matthew L. Anderson, Patricia D. Castro, Michael Ittmann, David Huntsman, Bernard Kohl, Xuan Le, Richard Thorp, Chris Andry, Elizabeth R. Duffy, Vladimir Lyadov, Oxana Paklina, Galiya Setdikova, Alexey Shabunin, Mikhail Tavobilov, Christopher McPherson, Ronald Warnick, Ross Berkowitz, Daniel Cramer, Colleen Feltmate, Neil Horowitz, Adam Kibel, Michael Muto, Chandrajit P. Raut, Andrei Malykh, Jill S. Barnholtz-Sloan, Wendi Barrett, Karen Devine, Jordonna Fulop, Quinn T. Ostrom, Kristen Shimmel, Yingli Wolinsky, Andrew E. Sloan, Agostino De Rose, Felice Giuliante, Marc Goodman, Beth Y. Karlan, Curt H. Hagedorn, John Eckman, Jodi Harr, Jerome Myers, Kelinda Tucker, Leigh Anne Zach, Brenda Deyarmin, Hai Hu, Leonid Kvecher, Caroline Larson, Richard J. Mural, Stella Somiari, Ales Vicha, Tomas Zelinka, Joseph Bennett, Mary Iacocca, Brenda Rabeno, Patricia Swanson, Mathieu Latour, Louis Lacombe, Bernard Têtu, Alain Bergeron, Mary McGraw, Susan M. Staugaitis, John Chabot, Hanina Hibshoosh, Antonia Sepulveda, Tao Su, Timothy Wang, Olga Potapova, Olga Voronina, Laurence Desjardins, Odette Mariani, Sergio Roman-Roman, Xavier Sastre, Marc-Henri Stern, Feixiong Cheng, Sabina Signoretti, Andrew Berchuck, Darell Bigner, Eric Lipp, Jeffrey Marks, Shannon McCall, Roger McLendon, Angeles Secord, Alexis Sharp, Madhusmita Behera, Daniel J. Brat, Amy Chen, Keith Delman, Seth Force, Fadlo Khuri, Kelly Magliocca, Shishir Maithel, Jeffrey J. Olson, Taofeek Owonikoko, Alan Pickens, Suresh Ramalingam, Dong M. Shin, Gabriel Sica, Erwin G. Van Meir, Hongzheng Zhang, Wil Eijckenboom, Ad Gillis, Esther Korpershoek, Leendert Looijenga, Wolter Oosterhuis, Hans Stoop, Kim E. van Kessel, Ellen C. Zwarthoff, Chiara Calatozzolo, Lucia Cuppini, Stefania Cuzzubbo, Francesco DiMeco, Gaetano Finocchiaro, Luca Mattei, Alessandro Perin, Bianca Pollo, Chu Chen, John Houck, Pawadee Lohavanichbutr, Arndt Hartmann, Christine Stoehr, Robert Stoehr, Helge Taubert, Sven Wach, Bernd Wullich, Witold Kycler, Dawid Murawa, Maciej Wiznerowicz, Ki Chung, W. Jeffrey Edenfield, Julie Martin, Eric Baudin, Glenn Bubley, Raphael Bueno, Assunta De Rienzo, William G. Richards, Steven Kalkanis, Tom Mikkelsen, Houtan Noushmehr, Lisa Scarpace, Nicolas Girard, Marta Aymerich, Elias Campo, Eva Giné, Armando López Guillermo, Nguyen Van Bang, Phan Thi Hanh, Bui Duc Phu, Yufang Tang, Howard Colman, Kimberley Evason, Peter R. Dottino, John A. Martignetti, Hani Gabra, Hartmut Juhl, Teniola Akeredolu, Serghei Stepa, Dave Hoon, Keunsoo Ahn, Koo Jeong Kang, Felix Beuschlein, Anne Breggia, Michael Birrer, Debra Bell, Mitesh Borad, Alan H. Bryce, Erik Castle, Vishal Chandan, John Cheville, John A. Copland, Michael Farnell, Thomas Flotte, Nasra Giama, Thai Ho, Michael Kendrick, Jean-Pierre Kocher, Karla Kopp, Catherine Moser, David Nagorney, Daniel O’Brien, Brian Patrick O’Neill, Tushar Patel, Gloria Petersen, Florencia Que, Michael Rivera, Lewis Roberts, Robert Smallridge, Thomas Smyrk, Melissa Stanton, R. Houston Thompson, Michael Torbenson, Ju Dong Yang, Lizhi Zhang, Fadi Brimo, Jaffer A. Ajani, Ana Maria Angulo Gonzalez, Carmen Behrens, Jolanta Bondaruk, Russell Broaddus, Bogdan Czerniak, Bita Esmaeli, Junya Fujimoto, Jeffrey Gershenwald, Charles Guo, Alexander J. Lazar, Christopher Logothetis, Funda Meric-Bernstam, Cesar Moran, Lois Ramondetta, David Rice, Anil Sood, Pheroze Tamboli, Timothy Thompson, Patricia Troncoso, Anne Tsao, Ignacio Wistuba, Candace Carter, Lauren Haydu, Peter Hersey, Valerie Jakrot, Hojabr Kakavand, Richard Kefford, Kenneth Lee, Georgina Long, Graham Mann, Michael Quinn, Robyn Saw, Richard Scolyer, Kerwin Shannon, Andrew Spillane, Jonathan Stretch, Maria Synott, John Thompson, James Wilmott, Hikmat Al-Ahmadie, Timothy A. Chan, Ronald Ghossein, Anuradha Gopalan, Douglas A. Levine, Victor Reuter, Samuel Singer, Bhuvanesh Singh, Nguyen Viet Tien, Thomas Broudy, Cyrus Mirsaidi, Praveen Nair, Paul Drwiega, Judy Miller, Jennifer Smith, Howard Zaren, Joong-Won Park, Nguyen Phi Hung, Electron Kebebew, W. Marston Linehan, Adam R. Metwalli, Karel Pacak, Peter A. Pinto, Mark Schiffman, Laura S. Schmidt, Cathy D. Vocke, Nicolas Wentzensen, Robert Worrell, Hannah Yang, Marc Moncrieff, Chandra Goparaju, Jonathan Melamed, Harvey Pass, Natalia Botnariuc, Irina Caraman, Mircea Cernat, Inga Chemencedji, Adrian Clipca, Serghei Doruc, Ghenadie Gorincioi, Sergiu Mura, Maria Pirtac, Irina Stancul, Diana Tcaciuc, Monique Albert, Iakovina Alexopoulou, Angel Arnaout, John Bartlett, Jay Engel, Sebastien Gilbert, Jeremy Parfitt, Harman Sekhon, George Thomas, Doris M. Rassl, Robert C. Rintoul, Carlo Bifulco, Raina Tamakawa, Walter Urba, Nicholas Hayward, Henri Timmers, Anna Antenucci, Francesco Facciolo, Gianluca Grazi, Mirella Marino, Roberta Merola, Ronald de Krijger, Anne-Paule Gimenez-Roqueplo, Alain Piché, Simone Chevalier, Ginette McKercher, Kivanc Birsoy, Gene Barnett, Cathy Brewer, Carol Farver, Theresa Naska, Nathan A. Pennell, Daniel Raymond, Cathy Schilero, Kathy Smolenski, Felicia Williams, Carl Morrison, Jeffrey A. Borgia, Michael J. Liptay, Mark Pool, Christopher W. Seder, Kerstin Junker, Larsson Omberg, Mikhail Dinkin, George Manikhas, Domenico Alvaro, Maria Consiglia Bragazzi, Vincenzo Cardinale, Guido Carpino, Eugenio Gaudio, David Chesla, Sandra Cottingham, Michael Dubina, Fedor Moiseenko, Renumathy Dhanasekaran, Karl-Friedrich Becker, Klaus-Peter Janssen, Julia Slotta-Huspenina, Mohamed H. Abdel-Rahman, Dina Aziz, Sue Bell, Colleen M. Cebulla, Amy Davis, Rebecca Duell, J. Bradley Elder, Joe Hilty, Bahavna Kumar, James Lang, Norman L. Lehman, Randy Mandt, Phuong Nguyen, Robert Pilarski, Karan Rai, Lynn Schoenfield, Kelly Senecal, Paul Wakely, Paul Hansen, Ronald Lechan, James Powers, Arthur Tischler, William E. Grizzle, Katherine C. Sexton, Alison Kastl, Joel Henderson, Sima Porten, Jens Waldmann, Martin Fassnacht, Sylvia L. Asa, Dirk Schadendorf, Marta Couce, Markus Graefen, Hartwig Huland, Guido Sauter, Thorsten Schlomm, Ronald Simon, Pierre Tennstedt, Oluwole Olabode, Mark Nelson, Oliver Bathe, Peter R. Carroll, June M. Chan, Philip Disaia, Pat Glenn, Robin K. Kelley, Charles N. Landen, Joanna Phillips, Michael Prados, Jeffry Simko, Karen Smith-McCune, Scott VandenBerg, Kevin Roggin, Ashley Fehrenbach, Ady Kendler, Suzanne Sifri, Ruth Steele, Antonio Jimeno, Francis Carey, Ian Forgie, Massimo Mannelli, Michael Carney, Brenda Hernandez, Benito Campos, Christel Herold-Mende, Christin Jungk, Andreas Unterberg, Andreas von Deimling, Aaron Bossler, Joseph Galbraith, Laura Jacobus, Michael Knudson, Tina Knutson, Deqin Ma, Mohammed Milhem, Rita Sigmund, Andrew K. Godwin, Rashna Madan, Howard G. Rosenthal, Clement Adebamowo, Sally N. Adebamowo, Alex Boussioutas, David Beer, Thomas Giordano, Anne-Marie Mes-Masson, Fred Saad, Therese Bocklage, Lisa Landrum, Robert Mannel, Kathleen Moore, Katherine Moxley, Russel Postier, Joan Walker, Rosemary Zuna, Michael Feldman, Federico Valdivieso, Rajiv Dhir, James Luketich, Edna M. Mora Pinero, Mario Quintero-Aguilo, Carlos Gilberto Carlotti, Jose Sebastião Dos Santos, Rafael Kemp, Ajith Sankarankuty, Daniela Tirapelli, James Catto, Kathy Agnew, Elizabeth Swisher, Jenette Creaney, Bruce Robinson, Carl Simon Shelley, Eryn M. Godwin, Sara Kendall, Cassaundra Shipman, Carol Bradford, Thomas Carey, Andrea Haddad, Jeffey Moyer, Lisa Peterson, Mark Prince, Laura Rozek, Gregory Wolf, Rayleen Bowman, Kwun M. Fong, Ian Yang, Robert Korst, W. Kimryn Rathmell, J. Leigh Fantacone-Campbell, Jeffrey A. Hooke, Albert J. Kovatich, Craig D. Shriver, John DiPersio, Bettina Drake, Ramaswamy Govindan, Sharon Heath, Timothy Ley, Brian Van Tine, Peter Westervelt, Mark A. Rubin, Jung Il Lee, Natália D. Aredes, Armaz Mariamidze, SAIC-F-Frederick, Inc, Leidos Biomedical Research, Inc., Wang Z., Yang B., Zhang M., Guo W., Wu Z., Wang Y., Jia L., Li S., Caesar-Johnson S.J., Demchok J.A., Felau I., Kasapi M., Ferguson M.L., Hutter C.M., Sofia H.J., Tarnuzzer R., Yang L., Zenklusen J.C., Zhang J.J., Chudamani S., Liu J., Lolla L., Naresh R., Pihl T., Sun Q., Wan Y., Wu Y., Cho J., DeFreitas T., Frazer S., Gehlenborg N., Getz G., Heiman D.I., Kim J., Lawrence M.S., Lin P., Meier S., Noble M.S., Saksena G., Voet D., Zhang H., Bernard B., Chambwe N., Dhankani V., Knijnenburg T., Kramer R., Leinonen K., Liu Y., Miller M., Reynolds S., Shmulevich I., Thorsson V., Zhang W., Akbani R., Broom B.M., Hegde A.M., Ju Z., Kanchi R.S., Korkut A., Li J., Liang H., Ling S., Liu W., Lu Y., Mills G.B., Ng K.-S., Rao A., Ryan M., Wang J., Weinstein J.N., Zhang J., Abeshouse A., Armenia J., Chakravarty D., Chatila W.K., Bruijn I., Gao J., Gross B.E., Heins Z.J., Kundra R., La K., Ladanyi M., Luna A., Nissan 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Subjects: 0301 basic medicine, breast cancer, CIMP, ENSG00000224271, EPIC1, LOC284930, long noncoding RNA, MYC, P21, TCGA pan-cancer, Cancer Research, PROTEIN, Cancer Genome Atlas Research Network, medicine.disease_cause, ANALYSES REVEAL, Epigenesis, Genetic, Mice, LS2_1, LS4_6, 610 Medicine & health, Promoter Regions, Genetic, GENE-EXPRESSION, Regulation of gene expression, FENÓTIPOS, Cell Cycle, METHYLATION, Cell cycle, Prognosis, Long non-coding RNA, Up-Regulation, TRANSCRIPTIONAL NETWORK, GENOME, Gene Expression Regulation, Neoplastic, SEQ, CpG site, Oncology, DNA methylation, Female, RNA, Long Noncoding, Life Sciences & Biomedicine, Breast Neoplasm, Human, Prognosi, Breast Neoplasms, Biology, BINDING-SITES, Article, NO, Proto-Oncogene Proteins c-myc, 03 medical and health sciences, Cell Line, Tumor, medicine, C-MYC, Animals, Humans, 1112 Oncology and Carcinogenesis, Epigenetics, Oncology & Carcinogenesis, Science & Technology, Binding Sites, Animal, Binding Site, Cancer, Cell Biology, DNA Methylation, medicine.disease, 030104 developmental biology, Cancer research, CpG Islands, CpG Island, Carcinogenesis, 1109 Neurosciences, Neoplasm Transplantation
Abstract: We characterized the epigenetic landscape of genes encoding long noncoding RNAs (lncRNAs) across 6,475 tumors and 455 cancer cell lines. In stark contrast to the CpG island hypermethylation phenotype in cancer, we observed a recurrent hypomethylation of 1,006 lncRNA genes in cancer, including EPIC1 (epigenetically-induced lncRNA1). Overexpression of EPIC1 is associated with poor prognosis in luminal B breast cancer patients and enhances tumor growth in vitro and in vivo. Mechanistically, EPIC1 promotes cell-cycle progression by interacting with MYC through EPIC1's 129–283 nt region. EPIC1 knockdown reduces the occupancy of MYC to its target genes (e.g., CDKN1A, CCNA2, CDC20, and CDC45). MYC depletion abolishes EPIC1's regulation of MYC target and luminal breast cancer tumorigenesis in vitro and in vivo. Wang et al. characterize the epigenetic landscape of lncRNAs genes across a large number of human tumors and cancer cell lines and observe recurrent hypomethylation of lncRNA genes, including EPIC1. EPIC1 RNA promotes cell-cycle progression by interacting with MYC and enhancing its binding to target genes.
Published: 2018
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165. Machine Learning Identifies Stemness Features Associated with Oncogenic Dedifferentiation

Author: Tathiane M. Malta, Artem Sokolov, Andrew J. Gentles, Tomasz Burzykowski, Laila Poisson, John N. Weinstein, Bożena Kamińska, Joerg Huelsken, Larsson Omberg, Olivier Gevaert, Antonio Colaprico, Patrycja Czerwińska, Sylwia Mazurek, Lopa Mishra, Holger Heyn, Alex Krasnitz, Andrew K. Godwin, Alexander J. Lazar, Joshua M. Stuart, Katherine A. Hoadley, Peter W. Laird, Houtan Noushmehr, Maciej Wiznerowicz, Samantha J. Caesar-Johnson, John A. Demchok, Ina Felau, Melpomeni Kasapi, Martin L. Ferguson, Carolyn M. Hutter, Heidi J. Sofia, Roy Tarnuzzer, Zhining Wang, Liming Yang, Jean C. Zenklusen, Jiashan (Julia) Zhang, Sudha Chudamani, Jia Liu, Laxmi Lolla, Rashi Naresh, Todd Pihl, Qiang Sun, Yunhu Wan, Ye Wu, Juok Cho, Timothy DeFreitas, Scott Frazer, Nils Gehlenborg, Gad Getz, David I. Heiman, Jaegil Kim, Michael S. Lawrence, Pei Lin, Sam Meier, Michael S. Noble, Gordon Saksena, Doug Voet, Hailei Zhang, Brady Bernard, Nyasha Chambwe, Varsha Dhankani, Theo Knijnenburg, Roger Kramer, Kalle Leinonen, Yuexin Liu, Michael Miller, Sheila Reynolds, Ilya Shmulevich, Vesteinn Thorsson, Wei Zhang, Rehan Akbani, Bradley M. Broom, Apurva M. Hegde, Zhenlin Ju, Rupa S. Kanchi, Anil Korkut, Jun Li, Han Liang, Shiyun Ling, Wenbin Liu, Yiling Lu, Gordon B. Mills, Kwok-Shing Ng, Arvind Rao, Michael Ryan, Jing Wang, Jiexin Zhang, Adam Abeshouse, Joshua Armenia, Debyani Chakravarty, Walid K. Chatila, Ino de Bruijn, Jianjiong Gao, Benjamin E. Gross, Zachary J. Heins, Ritika Kundra, Konnor La, Marc Ladanyi, Augustin Luna, Moriah G. Nissan, Angelica Ochoa, Sarah M. Phillips, Ed Reznik, Francisco Sanchez-Vega, Chris Sander, Nikolaus Schultz, Robert Sheridan, S. Onur Sumer, Yichao Sun, Barry S. Taylor, Jioajiao Wang, Hongxin Zhang, Pavana Anur, Myron Peto, Paul Spellman, Christopher Benz, Christopher K. Wong, Christina Yau, D. Neil Hayes, Joel S. Parker, Matthew D. Wilkerson, Adrian Ally, Miruna Balasundaram, Reanne Bowlby, Denise Brooks, Rebecca Carlsen, Eric Chuah, Noreen Dhalla, Robert Holt, Steven J.M. Jones, Katayoon Kasaian, Darlene Lee, Yussanne Ma, Marco A. Marra, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Karen Mungall, A. Gordon Robertson, Sara Sadeghi, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Nina Thiessen, Kane Tse, Tina Wong, Ashton C. Berger, Rameen Beroukhim, Andrew D. Cherniack, Carrie Cibulskis, Stacey B. Gabriel, Galen F. Gao, Gavin Ha, Matthew Meyerson, Steven E. Schumacher, Juliann Shih, Melanie H. Kucherlapati, Raju S. Kucherlapati, Stephen Baylin, Leslie Cope, Ludmila Danilova, Moiz S. Bootwalla, Phillip H. Lai, Dennis T. Maglinte, David J. Van Den Berg, Daniel J. Weisenberger, J. Todd Auman, Saianand Balu, Tom Bodenheimer, Cheng Fan, Alan P. Hoyle, Stuart R. Jefferys, Corbin D. Jones, Shaowu Meng, Piotr A. Mieczkowski, Lisle E. Mose, Amy H. Perou, Charles M. 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Subjects: 0301 basic medicine, Carcinogenesis, pan-cancer, Cancer Genome Atlas Research Network, medicine.disease_cause, Biochemistry, epigenomic, Epigenesis, Genetic, genomic, Machine Learning, GENE-EXPRESSION SIGNATURE, TUMOR, Neoplasms, Databases, Genetic, Tumor Microenvironment, LS4_6, Stemness, Neoplasm Metastasis, 610 Medicine & health, Induced pluripotent stem cell, 11 Medical and Health Sciences, Carcinogenesi, Epigenomics, Cancer stem cells, Stem Cells, PROLIFERATION, MicroRNA, Sciences bio-médicales et agricoles, CANCER, stemne, Neoplasm Metastasi, CONNECTIVITY MAP, ALGORITMOS, Stem cell, Life Sciences & Biomedicine, Human, Biochemistry & Molecular Biology, cancer stem cell, The Cancer Genome Atlas, Biology, Article, General Biochemistry, Genetics and Molecular Biology, NO, ANNEXIN 1, 03 medical and health sciences, Stem Cell, Cancer stem cell, medicine, Humans, Epigenetics, EMBRYONIC STEM, Tumor microenvironment, Science & Technology, Biochemistry, Genetics and Molecular Biology(all), dedifferentiation, Cell Biology, 06 Biological Sciences, Cell Dedifferentiation, DNA Methylation, Immune checkpoint, SELF-RENEWAL, MicroRNAs, 030104 developmental biology, CELLS, Cancer research, Neoplasm, OVEREXPRESSION, The Cancer Genome Atla, Transcriptome, cancer stem cells, machine learning, stemness, Genetics and Molecular Biology(all), Developmental Biology
Abstract: 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. Stemness features extracted from transcriptomic and epigenetic data from TCGA tumors reveal novel biological and clinical insight, as well as potential drug targets for anti-cancer therapies., 0, info:eu-repo/semantics/published
Published: 2018
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166. Integrated Genomic Analysis of the Ubiquitin Pathway across Cancer Types

Author: Zhongqi Ge, Jake S. Leighton, Yumeng Wang, Xinxin Peng, Zhongyuan Chen, Hu Chen, Yutong Sun, Fan Yao, Jun Li, Huiwen Zhang, Jianfang Liu, Craig D. Shriver, Hai Hu, Helen Piwnica-Worms, Li Ma, Han Liang, Samantha J. Caesar-Johnson, John A. Demchok, Ina Felau, Melpomeni Kasapi, Martin L. Ferguson, Carolyn M. Hutter, Heidi J. Sofia, Roy Tarnuzzer, Zhining Wang, Liming Yang, Jean C. Zenklusen, Jiashan (Julia) Zhang, Sudha Chudamani, Jia Liu, Laxmi Lolla, Rashi Naresh, Todd Pihl, Qiang Sun, Yunhu Wan, Ye Wu, Juok Cho, Timothy DeFreitas, Scott Frazer, Nils Gehlenborg, Gad Getz, David I. Heiman, Jaegil Kim, Michael S. Lawrence, Pei Lin, Sam Meier, Michael S. Noble, Gordon Saksena, Doug Voet, Hailei Zhang, Brady Bernard, Nyasha Chambwe, Varsha Dhankani, Theo Knijnenburg, Roger Kramer, Kalle Leinonen, Yuexin Liu, Michael Miller, Sheila Reynolds, Ilya Shmulevich, Vesteinn Thorsson, Wei Zhang, Rehan Akbani, Bradley M. Broom, Apurva M. Hegde, Zhenlin Ju, Rupa S. Kanchi, Anil Korkut, Shiyun Ling, Wenbin Liu, Yiling Lu, Gordon B. Mills, Kwok-Shing Ng, Arvind Rao, Michael Ryan, Jing Wang, John N. Weinstein, Jiexin Zhang, Adam Abeshouse, Joshua Armenia, Debyani Chakravarty, Walid K. Chatila, Ino de Bruijn, Jianjiong Gao, Benjamin E. Gross, Zachary J. Heins, Ritika Kundra, Konnor La, Marc Ladanyi, Augustin Luna, Moriah G. Nissan, Angelica Ochoa, Sarah M. Phillips, Ed Reznik, Francisco Sanchez-Vega, Chris Sander, Nikolaus Schultz, Robert Sheridan, S. Onur Sumer, Yichao Sun, Barry S. Taylor, Jioajiao Wang, Hongxin Zhang, Pavana Anur, Myron Peto, Paul Spellman, Christopher Benz, Joshua M. Stuart, Christopher K. Wong, Christina Yau, D. Neil Hayes, Joel S. Parker, Matthew D. Wilkerson, Adrian Ally, Miruna Balasundaram, Reanne Bowlby, Denise Brooks, Rebecca Carlsen, Eric Chuah, Noreen Dhalla, Robert Holt, Steven J.M. Jones, Katayoon Kasaian, Darlene Lee, Yussanne Ma, Marco A. Marra, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Karen Mungall, A. 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Copland, Michael Farnell, Thomas Flotte, Nasra Giama, Thai Ho, Michael Kendrick, Jean-Pierre Kocher, Karla Kopp, Catherine Moser, David Nagorney, Daniel O’Brien, Brian Patrick O’Neill, Tushar Patel, Gloria Petersen, Florencia Que, Michael Rivera, Lewis Roberts, Robert Smallridge, Thomas Smyrk, Melissa Stanton, R. Houston Thompson, Michael Torbenson, Ju Dong Yang, Lizhi Zhang, Fadi Brimo, Jaffer A. Ajani, Ana Maria Angulo Gonzalez, Carmen Behrens, Jolanta Bondaruk, Russell Broaddus, Bogdan Czerniak, Bita Esmaeli, Junya Fujimoto, Jeffrey Gershenwald, Charles Guo, Alexander J. Lazar, Christopher Logothetis, Funda Meric-Bernstam, Cesar Moran, Lois Ramondetta, David Rice, Anil Sood, Pheroze Tamboli, Timothy Thompson, Patricia Troncoso, Anne Tsao, Ignacio Wistuba, Candace Carter, Lauren Haydu, Peter Hersey, Valerie Jakrot, Hojabr Kakavand, Richard Kefford, Kenneth Lee, Georgina Long, Graham Mann, Michael Quinn, Robyn Saw, Richard Scolyer, Kerwin Shannon, Andrew Spillane, Jonathan Stretch, Maria Synott, John Thompson, James Wilmott, Hikmat Al-Ahmadie, Timothy A. Chan, Ronald Ghossein, Anuradha Gopalan, Douglas A. Levine, Victor Reuter, Samuel Singer, Bhuvanesh Singh, Nguyen Viet Tien, Thomas Broudy, Cyrus Mirsaidi, Praveen Nair, Paul Drwiega, Judy Miller, Jennifer Smith, Howard Zaren, Joong-Won Park, Nguyen Phi Hung, Electron Kebebew, W. Marston Linehan, Adam R. Metwalli, Karel Pacak, Peter A. Pinto, Mark Schiffman, Laura S. Schmidt, Cathy D. Vocke, Nicolas Wentzensen, Robert Worrell, Hannah Yang, Marc Moncrieff, Chandra Goparaju, Jonathan Melamed, Harvey Pass, Natalia Botnariuc, Irina Caraman, Mircea Cernat, Inga Chemencedji, Adrian Clipca, Serghei Doruc, Ghenadie Gorincioi, Sergiu Mura, Maria Pirtac, Irina Stancul, Diana Tcaciuc, Monique Albert, Iakovina Alexopoulou, Angel Arnaout, John Bartlett, Jay Engel, Sebastien Gilbert, Jeremy Parfitt, Harman Sekhon, George Thomas, Doris M. Rassl, Robert C. Rintoul, Carlo Bifulco, Raina Tamakawa, Walter Urba, Nicholas Hayward, Henri Timmers, Anna Antenucci, Francesco Facciolo, Gianluca Grazi, Mirella Marino, Roberta Merola, Ronald de Krijger, Anne-Paule Gimenez-Roqueplo, Alain Piché, Simone Chevalier, Ginette McKercher, Kivanc Birsoy, Gene Barnett, Cathy Brewer, Carol Farver, Theresa Naska, Nathan A. Pennell, Daniel Raymond, Cathy Schilero, Kathy Smolenski, Felicia Williams, Carl Morrison, Jeffrey A. Borgia, Michael J. Liptay, Mark Pool, Christopher W. Seder, Kerstin Junker, Larsson Omberg, Mikhail Dinkin, George Manikhas, Domenico Alvaro, Maria Consiglia Bragazzi, Vincenzo Cardinale, Guido Carpino, Eugenio Gaudio, David Chesla, Sandra Cottingham, Michael Dubina, Fedor Moiseenko, Renumathy Dhanasekaran, Karl-Friedrich Becker, Klaus-Peter Janssen, Julia Slotta-Huspenina, Mohamed H. Abdel-Rahman, Dina Aziz, Sue Bell, Colleen M. Cebulla, Amy Davis, Rebecca Duell, J. Bradley Elder, Joe Hilty, Bahavna Kumar, James Lang, Norman L. Lehman, Randy Mandt, Phuong Nguyen, Robert Pilarski, Karan Rai, Lynn Schoenfield, Kelly Senecal, Paul Wakely, Paul Hansen, Ronald Lechan, James Powers, Arthur Tischler, William E. Grizzle, Katherine C. Sexton, Alison Kastl, Joel Henderson, Sima Porten, Jens Waldmann, Martin Fassnacht, Sylvia L. Asa, Dirk Schadendorf, Marta Couce, Markus Graefen, Hartwig Huland, Guido Sauter, Thorsten Schlomm, Ronald Simon, Pierre Tennstedt, Oluwole Olabode, Mark Nelson, Oliver Bathe, Peter R. Carroll, June M. Chan, Philip Disaia, Pat Glenn, Robin K. Kelley, Charles N. Landen, Joanna Phillips, Michael Prados, Jeffry Simko, Karen Smith-McCune, Scott VandenBerg, Kevin Roggin, Ashley Fehrenbach, Ady Kendler, Suzanne Sifri, Ruth Steele, Antonio Jimeno, Francis Carey, Ian Forgie, Massimo Mannelli, Michael Carney, Brenda Hernandez, Benito Campos, Christel Herold-Mende, Christin Jungk, Andreas Unterberg, Andreas von Deimling, Aaron Bossler, Joseph Galbraith, Laura Jacobus, Michael Knudson, Tina Knutson, Deqin Ma, Mohammed Milhem, Rita Sigmund, Andrew K. Godwin, Rashna Madan, Howard G. Rosenthal, Clement Adebamowo, Sally N. Adebamowo, Alex Boussioutas, David Beer, Thomas Giordano, Anne-Marie Mes-Masson, Fred Saad, Therese Bocklage, Lisa Landrum, Robert Mannel, Kathleen Moore, Katherine Moxley, Russel Postier, Joan Walker, Rosemary Zuna, Michael Feldman, Federico Valdivieso, Rajiv Dhir, James Luketich, Edna M. Mora Pinero, Mario Quintero-Aguilo, Carlos Gilberto Carlotti, Jose Sebastião Dos Santos, Rafael Kemp, Ajith Sankarankuty, Daniela Tirapelli, James Catto, Kathy Agnew, Elizabeth Swisher, Jenette Creaney, Bruce Robinson, Carl Simon Shelley, Eryn M. Godwin, Sara Kendall, Cassaundra Shipman, Carol Bradford, Thomas Carey, Andrea Haddad, Jeffey Moyer, Lisa Peterson, Mark Prince, Laura Rozek, Gregory Wolf, Rayleen Bowman, Kwun M. Fong, Ian Yang, Robert Korst, W. Kimryn Rathmell, J. Leigh Fantacone-Campbell, Jeffrey A. Hooke, Albert J. Kovatich, John DiPersio, Bettina Drake, Ramaswamy Govindan, Sharon Heath, Timothy Ley, Brian Van Tine, Peter Westervelt, Mark A. Rubin, Jung Il Lee, Natália D. Aredes, Armaz Mariamidze, SAIC-F-Frederick, Inc, and Leidos Biomedical Research, Inc.
Subjects: Genetics and Molecular Biology (all), 0301 basic medicine, PTEN, pan-cancer analysis, F-BOX PROTEIN, Cancer Genome Atlas Research Network, therapeutic targets, Biochemistry, Genome, Deubiquitinating enzyme, ANTAGONISTS, Ubiquitin, CYCLIN-E, Neoplasms, PHOSPHORYLATION, 610 Medicine & health, lcsh:QH301-705.5, LIGASE, Oncogene Proteins, Genomics, Gene Expression Regulation, Neoplastic, biomarker, Mdm2, ubiquitin pathway, Life Sciences & Biomedicine, Metabolic Networks and Pathways, DNA repair, The Cancer Genome Atlas, Computational biology, Biology, cancer prognosis, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, MDM2, FBXW7, Cell Line, Tumor, Humans, Gene, Science & Technology, Genome, Human, RECOGNITION, Ubiquitination, Cell Biology, DEGRADATION, Protein ubiquitination, 030104 developmental biology, lcsh:Biology (General), tumor subtype, Biochemistry, Genetics and Molecular Biology (all), biology.protein, DEUBIQUITINATING ENZYMES, PROGNÓSTICO
Abstract: Summary: Protein ubiquitination is a dynamic and reversible process of adding single ubiquitin molecules or various ubiquitin chains to target proteins. Here, using multidimensional omic data of 9,125 tumor samples across 33 cancer types from The Cancer Genome Atlas, we perform comprehensive molecular characterization of 929 ubiquitin-related genes and 95 deubiquitinase genes. Among them, we systematically identify top somatic driver candidates, including mutated FBXW7 with cancer-type-specific patterns and amplified MDM2 showing a mutually exclusive pattern with BRAF mutations. Ubiquitin pathway genes tend to be upregulated in cancer mediated by diverse mechanisms. By integrating pan-cancer multiomic data, we identify a group of tumor samples that exhibit worse prognosis. These samples are consistently associated with the upregulation of cell-cycle and DNA repair pathways, characterized by mutated TP53, MYC/TERT amplification, and APC/PTEN deletion. Our analysis highlights the importance of the ubiquitin pathway in cancer development and lays a foundation for developing relevant therapeutic strategies. : Ge et al. analyze a cohort of 9,125 TCGA samples across 33 cancer types to provide a comprehensive characterization of the ubiquitin pathway. They detect somatic driver candidates in the ubiquitin pathway and identify a cluster of patients with poor survival, highlighting the importance of this pathway in cancer development. Keywords: ubiquitin pathway, pan-cancer analysis, The Cancer Genome Atlas, tumor subtype, cancer prognosis, therapeutic targets, biomarker, FBXW7
Published: 2018
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167. Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Author: Franz X. Schaub, Varsha Dhankani, Ashton C. Berger, Mihir Trivedi, Anne B. Richardson, Reid Shaw, Wei Zhao, Xiaoyang Zhang, Andrea Ventura, Yuexin Liu, Donald E. Ayer, Peter J. Hurlin, Andrew D. Cherniack, Robert N. Eisenman, Brady Bernard, Carla Grandori, Samantha J. Caesar-Johnson, John A. Demchok, Ina Felau, Melpomeni Kasapi, Martin L. Ferguson, Carolyn M. Hutter, Heidi J. Sofia, Roy Tarnuzzer, Zhining Wang, Liming Yang, Jean C. Zenklusen, Jiashan (Julia) Zhang, Sudha Chudamani, Jia Liu, Laxmi Lolla, Rashi Naresh, Todd Pihl, Qiang Sun, Yunhu Wan, Ye Wu, Juok Cho, Timothy DeFreitas, Scott Frazer, Nils Gehlenborg, Gad Getz, David I. Heiman, Jaegil Kim, Michael S. Lawrence, Pei Lin, Sam Meier, Michael S. Noble, Gordon Saksena, Doug Voet, Hailei Zhang, Nyasha Chambwe, Theo Knijnenburg, Roger Kramer, Kalle Leinonen, Michael Miller, Sheila Reynolds, Ilya Shmulevich, Vesteinn Thorsson, Wei Zhang, Rehan Akbani, Bradley M. Broom, Apurva M. Hegde, Zhenlin Ju, Rupa S. Kanchi, Anil Korkut, Jun Li, Han Liang, Shiyun Ling, Wenbin Liu, Yiling Lu, Gordon B. Mills, Kwok-Shing Ng, Arvind Rao, Michael Ryan, Jing Wang, John N. Weinstein, Jiexin Zhang, Adam Abeshouse, Joshua Armenia, Debyani Chakravarty, Walid K. Chatila, Ino de Bruijn, Jianjiong Gao, Benjamin E. Gross, Zachary J. Heins, Ritika Kundra, Konnor La, Marc Ladanyi, Augustin Luna, Moriah G. Nissan, Angelica Ochoa, Sarah M. Phillips, Ed Reznik, Francisco Sanchez-Vega, Chris Sander, Nikolaus Schultz, Robert Sheridan, S. Onur Sumer, Yichao Sun, Barry S. Taylor, Jioajiao Wang, Hongxin Zhang, Pavana Anur, Myron Peto, Paul Spellman, Christopher Benz, Joshua M. Stuart, Christopher K. Wong, Christina Yau, D. Neil Hayes, Joel S. Parker, Matthew D. Wilkerson, Adrian Ally, Miruna Balasundaram, Reanne Bowlby, Denise Brooks, Rebecca Carlsen, Eric Chuah, Noreen Dhalla, Robert Holt, Steven J.M. Jones, Katayoon Kasaian, Darlene Lee, Yussanne Ma, Marco A. Marra, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Karen Mungall, A. Gordon Robertson, Sara Sadeghi, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Nina Thiessen, Kane Tse, Tina Wong, Rameen Beroukhim, Carrie Cibulskis, Stacey B. Gabriel, Galen F. Gao, Gavin Ha, Matthew Meyerson, Steven E. Schumacher, Juliann Shih, Melanie H. Kucherlapati, Raju S. Kucherlapati, Stephen Baylin, Leslie Cope, Ludmila Danilova, Moiz S. Bootwalla, Phillip H. Lai, Dennis T. Maglinte, David J. Van Den Berg, Daniel J. Weisenberger, J. Todd Auman, Saianand Balu, Tom Bodenheimer, Cheng Fan, Katherine A. Hoadley, Alan P. Hoyle, Stuart R. Jefferys, Corbin D. Jones, Shaowu Meng, Piotr A. Mieczkowski, Lisle E. Mose, Amy H. Perou, Charles M. Perou, Jeffrey Roach, Yan Shi, Janae V. Simons, Tara Skelly, Matthew G. Soloway, Donghui Tan, Umadevi Veluvolu, Huihui Fan, Toshinori Hinoue, Peter W. Laird, Hui Shen, Wanding Zhou, Michelle Bellair, Kyle Chang, Kyle Covington, Chad J. Creighton, Huyen Dinh, HarshaVardhan Doddapaneni, Lawrence A. Donehower, Jennifer Drummond, Richard A. Gibbs, Robert Glenn, Walker Hale, Yi Han, Jianhong Hu, Viktoriya Korchina, Sandra Lee, Lora Lewis, Wei Li, Xiuping Liu, Margaret Morgan, Donna Morton, Donna Muzny, Jireh Santibanez, Margi Sheth, Eve Shinbrot, Linghua Wang, Min Wang, David A. Wheeler, Liu Xi, Fengmei Zhao, Julian Hess, Elizabeth L. Appelbaum, Matthew Bailey, Matthew G. Cordes, Li Ding, Catrina C. Fronick, Lucinda A. Fulton, Robert S. Fulton, Cyriac Kandoth, Elaine R. Mardis, Michael D. McLellan, Christopher A. Miller, Heather K. Schmidt, Richard K. Wilson, Daniel Crain, Erin Curley, Johanna Gardner, Kevin Lau, David Mallery, Scott Morris, Joseph Paulauskis, Robert Penny, Candace Shelton, Troy Shelton, Mark Sherman, Eric Thompson, Peggy Yena, Jay Bowen, Julie M. Gastier-Foster, Mark Gerken, Kristen M. Leraas, Tara M. Lichtenberg, Nilsa C. Ramirez, Lisa Wise, Erik Zmuda, Niall Corcoran, Tony Costello, Christopher Hovens, Andre L. Carvalho, Ana C. de Carvalho, José H. Fregnani, Adhemar Longatto-Filho, Rui M. Reis, Cristovam Scapulatempo-Neto, Henrique C.S. Silveira, Daniel O. Vidal, Andrew Burnette, Jennifer Eschbacher, Beth Hermes, Ardene Noss, Rosy Singh, Matthew L. Anderson, Patricia D. Castro, Michael Ittmann, David Huntsman, Bernard Kohl, Xuan Le, Richard Thorp, Chris Andry, Elizabeth R. Duffy, Vladimir Lyadov, Oxana Paklina, Galiya Setdikova, Alexey Shabunin, Mikhail Tavobilov, Christopher McPherson, Ronald Warnick, Ross Berkowitz, Daniel Cramer, Colleen Feltmate, Neil Horowitz, Adam Kibel, Michael Muto, Chandrajit P. Raut, Andrei Malykh, Jill S. Barnholtz-Sloan, Wendi Barrett, Karen Devine, Jordonna Fulop, Quinn T. Ostrom, Kristen Shimmel, Yingli Wolinsky, Andrew E. Sloan, Agostino De Rose, Felice Giuliante, Marc Goodman, Beth Y. Karlan, Curt H. Hagedorn, John Eckman, Jodi Harr, Jerome Myers, Kelinda Tucker, Leigh Anne Zach, Brenda Deyarmin, Hai Hu, Leonid Kvecher, Caroline Larson, Richard J. Mural, Stella Somiari, Ales Vicha, Tomas Zelinka, Joseph Bennett, Mary Iacocca, Brenda Rabeno, Patricia Swanson, Mathieu Latour, Louis Lacombe, Bernard Têtu, Alain Bergeron, Mary McGraw, Susan M. Staugaitis, John Chabot, Hanina Hibshoosh, Antonia Sepulveda, Tao Su, Timothy Wang, Olga Potapova, Olga Voronina, Laurence Desjardins, Odette Mariani, Sergio Roman-Roman, Xavier Sastre, Marc-Henri Stern, Feixiong Cheng, Sabina Signoretti, Andrew Berchuck, Darell Bigner, Eric Lipp, Jeffrey Marks, Shannon McCall, Roger McLendon, Angeles Secord, Alexis Sharp, Madhusmita Behera, Daniel J. Brat, Amy Chen, Keith Delman, Seth Force, Fadlo Khuri, Kelly Magliocca, Shishir Maithel, Jeffrey J. Olson, Taofeek Owonikoko, Alan Pickens, Suresh Ramalingam, Dong M. Shin, Gabriel Sica, Erwin G. Van Meir, Hongzheng Zhang, Wil Eijckenboom, Ad Gillis, Esther Korpershoek, Leendert Looijenga, Wolter Oosterhuis, Hans Stoop, Kim E. van Kessel, Ellen C. Zwarthoff, Chiara Calatozzolo, Lucia Cuppini, Stefania Cuzzubbo, Francesco DiMeco, Gaetano Finocchiaro, Luca Mattei, Alessandro Perin, Bianca Pollo, Chu Chen, John Houck, Pawadee Lohavanichbutr, Arndt Hartmann, Christine Stoehr, Robert Stoehr, Helge Taubert, Sven Wach, Bernd Wullich, Witold Kycler, Dawid Murawa, Maciej Wiznerowicz, Ki Chung, W. Jeffrey Edenfield, Julie Martin, Eric Baudin, Glenn Bubley, Raphael Bueno, Assunta De Rienzo, William G. Richards, Steven Kalkanis, Tom Mikkelsen, Houtan Noushmehr, Lisa Scarpace, Nicolas Girard, Marta Aymerich, Elias Campo, Eva Giné, Armando López Guillermo, Nguyen Van Bang, Phan Thi Hanh, Bui Duc Phu, Yufang Tang, Howard Colman, Kimberley Evason, Peter R. Dottino, John A. Martignetti, Hani Gabra, Hartmut Juhl, Teniola Akeredolu, Serghei Stepa, Dave Hoon, Keunsoo Ahn, Koo Jeong Kang, Felix Beuschlein, Anne Breggia, Michael Birrer, Debra Bell, Mitesh Borad, Alan H. Bryce, Erik Castle, Vishal Chandan, John Cheville, John A. Copland, Michael Farnell, Thomas Flotte, Nasra Giama, Thai Ho, Michael Kendrick, Jean-Pierre Kocher, Karla Kopp, Catherine Moser, David Nagorney, Daniel O’Brien, Brian Patrick O’Neill, Tushar Patel, Gloria Petersen, Florencia Que, Michael Rivera, Lewis Roberts, Robert Smallridge, Thomas Smyrk, Melissa Stanton, R. Houston Thompson, Michael Torbenson, Ju Dong Yang, Lizhi Zhang, Fadi Brimo, Jaffer A. Ajani, Ana Maria Angulo Gonzalez, Carmen Behrens, Jolanta Bondaruk, Russell Broaddus, Bogdan Czerniak, Bita Esmaeli, Junya Fujimoto, Jeffrey Gershenwald, Charles Guo, Alexander J. Lazar, Christopher Logothetis, Funda Meric-Bernstam, Cesar Moran, Lois Ramondetta, David Rice, Anil Sood, Pheroze Tamboli, Timothy Thompson, Patricia Troncoso, Anne Tsao, Ignacio Wistuba, Candace Carter, Lauren Haydu, Peter Hersey, Valerie Jakrot, Hojabr Kakavand, Richard Kefford, Kenneth Lee, Georgina Long, Graham Mann, Michael Quinn, Robyn Saw, Richard Scolyer, Kerwin Shannon, Andrew Spillane, Jonathan Stretch, Maria Synott, John Thompson, James Wilmott, Hikmat Al-Ahmadie, Timothy A. Chan, Ronald Ghossein, Anuradha Gopalan, Douglas A. Levine, Victor Reuter, Samuel Singer, Bhuvanesh Singh, Nguyen Viet Tien, Thomas Broudy, Cyrus Mirsaidi, Praveen Nair, Paul Drwiega, Judy Miller, Jennifer Smith, Howard Zaren, Joong-Won Park, Nguyen Phi Hung, Electron Kebebew, W. Marston Linehan, Adam R. Metwalli, Karel Pacak, Peter A. Pinto, Mark Schiffman, Laura S. Schmidt, Cathy D. Vocke, Nicolas Wentzensen, Robert Worrell, Hannah Yang, Marc Moncrieff, Chandra Goparaju, Jonathan Melamed, Harvey Pass, Natalia Botnariuc, Irina Caraman, Mircea Cernat, Inga Chemencedji, Adrian Clipca, Serghei Doruc, Ghenadie Gorincioi, Sergiu Mura, Maria Pirtac, Irina Stancul, Diana Tcaciuc, Monique Albert, Iakovina Alexopoulou, Angel Arnaout, John Bartlett, Jay Engel, Sebastien Gilbert, Jeremy Parfitt, Harman Sekhon, George Thomas, Doris M. Rassl, Robert C. Rintoul, Carlo Bifulco, Raina Tamakawa, Walter Urba, Nicholas Hayward, Henri Timmers, Anna Antenucci, Francesco Facciolo, Gianluca Grazi, Mirella Marino, Roberta Merola, Ronald de Krijger, Anne-Paule Gimenez-Roqueplo, Alain Piché, Simone Chevalier, Ginette McKercher, Kivanc Birsoy, Gene Barnett, Cathy Brewer, Carol Farver, Theresa Naska, Nathan A. Pennell, Daniel Raymond, Cathy Schilero, Kathy Smolenski, Felicia Williams, Carl Morrison, Jeffrey A. Borgia, Michael J. Liptay, Mark Pool, Christopher W. Seder, Kerstin Junker, Larsson Omberg, Mikhail Dinkin, George Manikhas, Domenico Alvaro, Maria Consiglia Bragazzi, Vincenzo Cardinale, Guido Carpino, Eugenio Gaudio, David Chesla, Sandra Cottingham, Michael Dubina, Fedor Moiseenko, Renumathy Dhanasekaran, Karl-Friedrich Becker, Klaus-Peter Janssen, Julia Slotta-Huspenina, Mohamed H. Abdel-Rahman, Dina Aziz, Sue Bell, Colleen M. Cebulla, Amy Davis, Rebecca Duell, J. Bradley Elder, Joe Hilty, Bahavna Kumar, James Lang, Norman L. Lehman, Randy Mandt, Phuong Nguyen, Robert Pilarski, Karan Rai, Lynn Schoenfield, Kelly Senecal, Paul Wakely, Paul Hansen, Ronald Lechan, James Powers, Arthur Tischler, William E. Grizzle, Katherine C. Sexton, Alison Kastl, Joel Henderson, Sima Porten, Jens Waldmann, Martin Fassnacht, Sylvia L. Asa, Dirk Schadendorf, Marta Couce, Markus Graefen, Hartwig Huland, Guido Sauter, Thorsten Schlomm, Ronald Simon, Pierre Tennstedt, Oluwole Olabode, Mark Nelson, Oliver Bathe, Peter R. Carroll, June M. Chan, Philip Disaia, Pat Glenn, Robin K. Kelley, Charles N. Landen, Joanna Phillips, Michael Prados, Jeffry Simko, Karen Smith-McCune, Scott VandenBerg, Kevin Roggin, Ashley Fehrenbach, Ady Kendler, Suzanne Sifri, Ruth Steele, Antonio Jimeno, Francis Carey, Ian Forgie, Massimo Mannelli, Michael Carney, Brenda Hernandez, Benito Campos, Christel Herold-Mende, Christin Jungk, Andreas Unterberg, Andreas von Deimling, Aaron Bossler, Joseph Galbraith, Laura Jacobus, Michael Knudson, Tina Knutson, Deqin Ma, Mohammed Milhem, Rita Sigmund, Andrew K. Godwin, Rashna Madan, Howard G. Rosenthal, Clement Adebamowo, Sally N. Adebamowo, Alex Boussioutas, David Beer, Thomas Giordano, Anne-Marie Mes-Masson, Fred Saad, Therese Bocklage, Lisa Landrum, Robert Mannel, Kathleen Moore, Katherine Moxley, Russel Postier, Joan Walker, Rosemary Zuna, Michael Feldman, Federico Valdivieso, Rajiv Dhir, James Luketich, Edna M. Mora Pinero, Mario Quintero-Aguilo, Carlos Gilberto Carlotti, Jose Sebastião Dos Santos, Rafael Kemp, Ajith Sankarankuty, Daniela Tirapelli, James Catto, Kathy Agnew, Elizabeth Swisher, Jenette Creaney, Bruce Robinson, Carl Simon Shelley, Eryn M. Godwin, Sara Kendall, Cassaundra Shipman, Carol Bradford, Thomas Carey, Andrea Haddad, Jeffey Moyer, Lisa Peterson, Mark Prince, Laura Rozek, Gregory Wolf, Rayleen Bowman, Kwun M. Fong, Ian Yang, Robert Korst, W. Kimryn Rathmell, J. Leigh Fantacone-Campbell, Jeffrey A. Hooke, Albert J. Kovatich, Craig D. Shriver, John DiPersio, Bettina Drake, Ramaswamy Govindan, Sharon Heath, Timothy Ley, Brian Van Tine, Peter Westervelt, Mark A. Rubin, Jung Il Lee, Natália D. Aredes, Armaz Mariamidze, SAIC-F-Frederick, Inc, Leidos Biomedical Research, Inc., Schaub, Franz X, Dhankani, Varsha, Berger, Ashton C, Trivedi, Mihir, Richardson, Anne B, Shaw, Reid, Zhao, Wei, Zhang, Xiaoyang, Ventura, Andrea, Liu, Yuexin, Ayer, Donald E, Hurlin, Peter J, Cherniack, Andrew D, Eisenman, Robert N, Bernard, Brady, Grandori, Carla, Grazi GL, DIPARTIMENTO DI SCIENZE MEDICHE E CHIRURGICHE, Facolta' di MEDICINA e CHIRURGIA, and AREA MIN. 06 - Scienze mediche
Subjects: Proteomics, 0301 basic medicine, Carcinogenesis, Genes, myc, Basic helix-loop-helix leucine zipper transcription factors, medicine.disease_cause, Neoplasms, Basic Helix-Loop-Helix Transcription Factors, LS2_1, Cancer Genome Atlas Network, 2.1 Biological and endogenous factors, LS4_6, Proto-Oncogene Proteins c-myc, MAX MUTATIONS, Aetiology, 610 Medicine & health, IN-VIVO, Cancer, GENE-EXPRESSION, MYC genomic alterations, Tumor, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, MAX, MNT, TCGA, The Cancer Genome Atlas, Genomics, myc, Chromatin, MYC genomic alteration, Life Sciences & Biomedicine, Signal Transduction, COPY-NUMBER ALTERATION, Biochemistry & Molecular Biology, Histology, MIR-200 FAMILY, RNA-POLYMERASE-II, Biology, ONCOGENES, Article, NO, CELL-PROLIFERATION, Pathology and Forensic Medicine, 03 medical and health sciences, Genetics, Biomarkers, Tumor, C-MYC, medicine, Humans, PTEN, TRANSCRIPTIONAL REPRESSORS, Transcription factor, Gene, MESENCHYMAL TRANSITION, Science & Technology, Oncogene, Human Genome, Computational Biology, Oncogenes, Cell Biology, Repressor Proteins, 030104 developmental biology, Genes, 2734, Cancer research, biology.protein, Biochemistry and Cell Biology, Biomarkers, Transcription Factors
Abstract: none 17 si Although the MYC oncogene has been implicated in cancer, a systematic assessment of alterations of MYC, related transcription factors, and co-regulatory proteins, forming the proximal MYC network (PMN), across human cancers is lacking. Using computational approaches, we define genomic and proteomic features associated with MYC and the PMN across the 33 cancers of The Cancer Genome Atlas. Pan-cancer, 28% of all samples had at least one of the MYC paralogs amplified. In contrast, the MYC antagonists MGA and MNT were the most frequently mutated or deleted members, proposing a role as tumor suppressors. MYC alterations were mutually exclusive with PIK3CA, PTEN, APC, or BRAF alterations, suggesting that MYC is a distinct oncogenic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such as immune response and growth factor signaling; chromatin, translation, and DNA replication/repair were conserved pan-cancer. This analysis reveals insights into MYC biology and is a reference for biomarkers and therapeutics for cancers with alterations of MYC or the PMN. none Schaub, Franz X; Dhankani, Varsha; Berger, Ashton C; Trivedi, Mihir; Richardson, Anne B; Shaw, Reid; Zhao, Wei; Zhang, Xiaoyang; Ventura, Andrea; Liu, Yuexin; Ayer, Donald E; Hurlin, Peter J; Cherniack, Andrew D; Eisenman, Robert N; Bernard, Brady; Grandori, Carla; Grazi GL Schaub, Franz X; Dhankani, Varsha; Berger, Ashton C; Trivedi, Mihir; Richardson, Anne B; Shaw, Reid; Zhao, Wei; Zhang, Xiaoyang; Ventura, Andrea; Liu, Yuexin; Ayer, Donald E; Hurlin, Peter J; Cherniack, Andrew D; Eisenman, Robert N; Bernard, Brady; Grandori, Carla; Grazi GL
Published: 2018
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168. Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma

Author: Michele Ceccarelli, Floris P. Barthel, Tathiane M. Malta, Thais S. Sabedot, Sofie R. Salama, Bradley A. Murray, Olena Morozova, Yulia Newton, Amie Radenbaugh, Stefano M. Pagnotta, Samreen Anjum, Jiguang Wang, Ganiraju Manyam, Pietro Zoppoli, Shiyun Ling, Arjun A. Rao, Mia Grifford, Andrew D. Cherniack, Hailei Zhang, Laila Poisson, Carlos Gilberto Carlotti, Daniela Pretti da Cunha Tirapelli, Arvind Rao, Tom Mikkelsen, Ching C. Lau, W.K. Alfred Yung, Raul Rabadan, Jason Huse, Daniel J. Brat, Norman L. Lehman, Jill S. Barnholtz-Sloan, Siyuan Zheng, Kenneth Hess, Ganesh Rao, Matthew Meyerson, Rameen Beroukhim, Lee Cooper, Rehan Akbani, Margaret Wrensch, David Haussler, Kenneth D. Aldape, Peter W. Laird, David H. Gutmann, Houtan Noushmehr, Antonio Iavarone, Roel G.W. Verhaak, Harindra Arachchi, J. Todd Auman, Miruna Balasundaram, Saianand Balu, Gene Barnett, Stephen Baylin, Sue Bell, Christopher Benz, Natalie Bir, Keith L. Black, Tom Bodenheimer, Lori Boice, Moiz S. Bootwalla, Jay Bowen, Christopher A. Bristow, Yaron S.N. Butterfield, Qing-Rong Chen, Lynda Chin, Juok Cho, Eric Chuah, Sudha Chudamani, Simon G. Coetzee, Mark L. Cohen, Howard Colman, Marta Couce, Fulvio D’Angelo, Tanja Davidsen, Amy Davis, John A. Demchok, Karen Devine, Li Ding, Rebecca Duell, J. Bradley Elder, Jennifer M. Eschbacher, Ashley Fehrenbach, Martin Ferguson, Scott Frazer, Gregory Fuller, Jordonna Fulop, Stacey B. Gabriel, Luciano Garofano, Julie M. Gastier-Foster, Nils Gehlenborg, Mark Gerken, Gad Getz, Caterina Giannini, William J. Gibson, Angela Hadjipanayis, D. Neil Hayes, David I. Heiman, Beth Hermes, Joe Hilty, Katherine A. Hoadley, Alan P. Hoyle, Mei Huang, Stuart R. Jefferys, Corbin D. Jones, Steven J.M. Jones, Zhenlin Ju, Alison Kastl, Ady Kendler, Jaegil Kim, Raju Kucherlapati, Phillip H. Lai, Michael S. Lawrence, Semin Lee, Kristen M. Leraas, Tara M. Lichtenberg, Pei Lin, Yuexin Liu, Jia Liu, Julia Y. Ljubimova, Yiling Lu, Yussanne Ma, Dennis T. Maglinte, Harshad S. Mahadeshwar, Marco A. Marra, Mary McGraw, Christopher McPherson, Shaowu Meng, Piotr A. Mieczkowski, C. Ryan Miller, Gordon B. Mills, Richard A. Moore, Lisle E. Mose, Andrew J. Mungall, Rashi Naresh, Theresa Naska, Luciano Neder, Michael S. Noble, Ardene Noss, Brian Patrick O’Neill, Quinn T. Ostrom, Cheryl Palmer, Angeliki Pantazi, Michael Parfenov, Peter J. Park, Joel S. Parker, Charles M. Perou, Christopher R. Pierson, Todd Pihl, Alexei Protopopov, Nilsa C. Ramirez, W. Kimryn Rathmell, Xiaojia Ren, Jeffrey Roach, A. Gordon Robertson, Gordon Saksena, Jacqueline E. Schein, Steven E. Schumacher, Jonathan Seidman, Kelly Senecal, Sahil Seth, Hui Shen, Yan Shi, Juliann Shih, Kristen Shimmel, Hugues Sicotte, Suzanne Sifri, Tiago Silva, Janae V. Simons, Rosy Singh, Tara Skelly, Andrew E. Sloan, Heidi J. Sofia, Matthew G. Soloway, Xingzhi Song, Carrie Sougnez, Camila Souza, Susan M. Staugaitis, Huandong Sun, Charlie Sun, Donghui Tan, Jiabin Tang, Yufang Tang, Leigh Thorne, Felipe Amstalden Trevisan, Timothy Triche, David J. Van Den Berg, Umadevi Veluvolu, Doug Voet, Yunhu Wan, Zhining Wang, Ronald Warnick, John N. Weinstein, Daniel J. Weisenberger, Matthew D. Wilkerson, Felicia Williams, Lisa Wise, Yingli Wolinsky, Junyuan Wu, Andrew W. Xu, Lixing Yang, Liming Yang, Travis I. Zack, Jean C. Zenklusen, Jianhua Zhang, Wei Zhang, Jiashan Zhang, Erik Zmuda, Ceccarelli, M, Barthel, Fp, Malta, Tm, Sabedot, T, Salama, Sr, Murray, Ba, Morozova, O, Newton, Y, Radenbaugh, A, Pagnotta, Sm, Anjum, S, Wang, Jg, Manyam, G, Zoppoli, P, Ling, S, Rao, Aa, Grifford, M, Cherniack, Ad, Zhang, Hl, Poisson, L, Carlotti, Cg, Tirapelli, Dpd, Rao, A, Mikkelsen, T, Lau, Cc, Yung, Wka, Rabadan, R, Huse, J, Brat, Dj, Lehman, Nl, Barnholtz-Sloan, J, Zheng, S, Hess, K, Rao, G, Meyerson, M, Beroukhim, R, Cooper, L, Akbani, R, Wrensch, M, Haussler, D, Aldape, Kd, Laird, Pw, Gutmann, Dh, Noushmehr, H, Iavarone, A, Verhaak, Rgw, and Neurosurgery
Subjects: 0301 basic medicine, Adult, X-linked Nuclear Protein, Biology, General Biochemistry, Genetics and Molecular Biology, Article, Epigenesis, Genetic, Transcriptome, 03 medical and health sciences, Diffuse Glioma, Glioma, medicine, Cluster Analysis, Humans, Promoter Regions, Genetic, Gene, Telomerase, ATRX, Cell Proliferation, Pilocytic astrocytoma, Biochemistry, Genetics and Molecular Biology(all), Brain Neoplasms, MUTAÇÃO GENÉTICA, DNA Helicases, Nuclear Proteins, DNA Methylation, Middle Aged, Telomere, medicine.disease, Isocitrate Dehydrogenase, 3. Good health, 030104 developmental biology, DNA demethylation, DNA methylation, Mutation, Cancer research, Signal Transduction
Abstract: Therapy development for adult diffuse glioma is hindered by incomplete knowledge of somatic glioma driving alterations and suboptimal disease classification. We defined the complete set of genes associated with 1,122 diffuse grade II-III-IV gliomas from The Cancer Genome Atlas and used molecular profiles to improve disease classification, identify molecular correlations, and provide insights into the progression from low- to high-grade disease. Whole-genome sequencing data analysis determined that ATRX but not TERT promoter mutations are associated with increased telomere length. Recent advances in glioma classification based on IDH mutation and 1p/19q co-deletion status were recapitulated through analysis of DNA methylation profiles, which identified clinically relevant molecular subsets. A subtype of IDH mutant glioma was associated with DNA demethylation and poor outcome; a group of IDH-wild-type diffuse glioma showed molecular similarity to pilocytic astrocytoma and relatively favorable survival. Understanding of cohesive disease groups may aid improved clinical outcomes.
Published: 2016
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169. DNA defects, epigenetics, and gene expression in cancer-adjacent breast: A study from the cancer genome atlas

Author: Kimberly H. Allison, Daniel C. Koboldt, Hui Shen, Melissa A. Troester, Swapna Mahurkar, Christina Yau, Monica D'Arcy, Margi Sheth, Rupninder Sandhu, Li Ding, Charles M. Perou, Matthew D. Wilkerson, Christopher C. Benz, A. Gordon Robertson, Andrew D. Cherniack, Chip Stewart, Peter W. Laird, Andrew H. Beck, Nicole B. Johnson, Katherine A. Hoadley, Jay Bowen, and E. Shelley Hwang
Subjects: 0301 basic medicine, Population, Biology, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Breast cancer, Gene expression, microRNA, medicine, Pharmacology (medical), Radiology, Nuclear Medicine and imaging, Epigenetics, education, Messenger RNA, education.field_of_study, medicine.disease, Molecular biology, 3. Good health, 030104 developmental biology, Oncology, chemistry, 030220 oncology & carcinogenesis, DNA methylation, Cancer research, DNA
Abstract: Recurrence rates after breast-conserving therapy may depend on genomic characteristics of cancer-adjacent, benign-appearing tissue. Studies have not evaluated recurrence in association with multiple genomic characteristics of cancer-adjacent breast tissue. To estimate the prevalence of DNA defects and RNA expression subtypes in cancer-adjacent, benign-appearing breast tissue at least 2 cm from the tumor margin, cancer-adjacent, pathologically well-characterized, benign-appearing breast tissue specimens from The Cancer Genome Atlas project were analyzed for DNA sequence, copy-number variation, DNA methylation, messenger RNA (mRNA) sequence, and mRNA/microRNA expression. Additional samples were also analyzed by at least one of these genomic data types and associations between genomic characteristics of normal tissue and overall survival were assessed. Approximately 40% of cancer-adjacent, benign-appearing tissues harbored genomic defects in DNA copy number, sequence, methylation, or in RNA sequence, although these defects did not significantly predict 10-year overall survival. Two mRNA/microRNA expression phenotypes were observed, including an active mRNA subtype that was identified in 40% of samples. Controlling for tumor characteristics and the presence of genomic defects, this active subtype was associated with significantly worse 10-year survival among estrogen receptor (ER)-positive cases. This multi-platform analysis of breast cancer-adjacent samples produced genomic findings consistent with current surgical margin guidelines, and provides evidence that extratumoral RNA expression patterns in cancer-adjacent tissue predict overall survival among patients with ER-positive disease. RNA expression patterns in the breast tissue adjacent to where tumors are surgically removed are linked to patient survival outcomes. A research team led by Melissa Troester from the University of North Carolina at Chapel Hill, USA, looked for genomic alterations in the healthy, benign-looking breast tissue found more than 2 centimeters from the margin of where cancer had been cut out and treated with radiation. Approximately 40% of the 142 tissue samples analyzed harbored defects in DNA copy number, sequence, methylation, or RNA sequence. However, the only characteristic significantly associated with 10-year survival rates in patients was a particular expression profile of messenger RNA known as “active” and this connection held up only in women with a subtype of breast cancer called ER-positive. In this population, RNA profiling could help predict survival outcomes.
Published: 2016
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170. Oncometabolite D-2-Hydroxyglutarate Inhibits ALKBH DNA Repair Enzymes and Sensitizes IDH Mutant Cells to Alkylating Agents

Author: Lei Zhang, Katherine A. Hoadley, Charles M. Perou, Kun-Liang Guan, Matthew D. Wilkerson, Jing Wu, Dan Ye, Shenghong Ma, Pu Wang, Jun Yao, and Yue Xiong
Subjects: DNA Repair, Mutant, Medical Physiology, medicine.disease_cause, chemistry.chemical_compound, RNA, Small Interfering, lcsh:QH301-705.5, Cancer, Mutation, Tumor, biology, Isocitrate Dehydrogenase, 3. Good health, Ketoglutaric Acids, RNA Interference, AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase, medicine.drug, Protein Binding, Alkylating Agents, DNA damage, DNA repair, AlkB, Small Interfering, Article, General Biochemistry, Genetics and Molecular Biology, Cell Line, Dioxygenases, Glutarates, Rare Diseases, Cell Line, Tumor, medicine, Genetics, Humans, Busulfan, AlkB Homolog 2, AlkB Homolog 3, AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase, Neurosciences, Lomustine, Alpha-Ketoglutarate-Dependent Dioxygenase, Molecular biology, Brain Disorders, Brain Cancer, DNA Repair Enzymes, chemistry, lcsh:Biology (General), Cancer research, biology.protein, RNA, Biochemistry and Cell Biology, Carcinogenesis, DNA, DNA Damage
Abstract: SummaryChemotherapy of a combination of DNA alkylating agents, procarbazine and lomustine (CCNU), and a microtubule poison, vincristine, offers a significant benefit to a subset of glioma patients. The benefit of this regimen, known as PCV, was recently linked to IDH mutation that occurs frequently in glioma and produces D-2-hydroxyglutarate (D-2-HG), a competitive inhibitor of α-ketoglutarate (α-KG). We report here that D-2-HG inhibits the α-KG-dependent alkB homolog (ALKBH) DNA repair enzymes. Cells expressing mutant IDH display reduced repair kinetics, accumulate more DNA damages, and are sensitized to alkylating agents. The observed sensitization to alkylating agents requires the catalytic activity of mutant IDH to produce D-2-HG and can be reversed by the deletion of mutant IDH allele or overexpression of ALKBH2 or AKLBH3. Our results suggest that impairment of DNA repair may contribute to tumorigenesis driven by IDH mutations and that alkylating agents may merit exploration for treating IDH-mutated cancer patients.
Published: 2015

171. Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma

Author: Thai H. Ho, Tina Wong, Donna Morton, Benjamin J. Raphael, Lora Lewis, Carrie Sougnez, Noreen Dhalla, Candace Shelton, Lori Boice, Bhavani Krishnan, J. Todd Auman, Joel Nelson, Jodi K. Maranchie, Saianand Balu, Chad J. Creighton, Min Wang, Brenda Ayala, Monique Albert, Maria Merino, Christopher J. Ricketts, Mark D.M. Leiserson, Michael Lobis, Nicholas J. Petrelli, Jiashan Zhang, Cynthia Winemiller, Angela Tam, Tom Bodenheimer, Payal Sipahimalani, Divya Kalra, W. Kimryn Rathmell, W. Troy Shelton, Amanda Clarke, David Mallery, Sudha Chudamani, Victor E. Reuter, Leigh Anne Zach, Laxmi Lolla, Kristen M. Leraas, Sara Sadeghi, Sabina Signoretti, Walker Hale, Janae V. Simons, Jeffrey Roach, Jie Li, Andrew J. Mungall, Roni J. Bollag, Adrian Ally, David Van Den Berg, Qiang Sun, Matthew G. Soloway, Ed Reznik, Joel Slaton, Laura S. Schmidt, Lisa Wise, R. Houston Thompson, Jingchun Zhu, Michael Mayo, Gordon B. Mills, Benjamin Davies, Ramaprasad Srinivasan, Donald P. Bottaro, Yan Shi, Nilsa C. Ramirez, Rashi Naresh, Yiling Lu, Peter W. Laird, Jeremiah J. Andersen, Richard A. Gibbs, Bradley A. Murray, Erik Zmuda, Kenneth Burnett, Steven E. Schumacher, Han Liang, Katherine A. Hoadley, Cathy D. Vocke, Toni K. Choueiri, Scott L. Carter, Scott McMeekin, Yussanne Ma, Joseph Paulauskis, Jerome Myers, Ronald L. Hrebinko, Phillip H. Lai, Leigh B. Thorne, Brian Shuch, Junyuan Wu, Katayoon Kasaian, Nandita Barnabas, Denise Brooks, Heidi J. Sofia, David A. Wheeler, Daniel J. Weisenberger, Nina Thiessen, Mark Gerken, A. Ari Hakimi, Yaron S.N. Butterfield, Mary Iacocca, Matthew Meyerson, John A. Demchok, Gordon Saksena, Tara Skelly, Corbin D. Jones, Abu Amar M. Al Mamun, Sheldon I. Bastacky, Liu Xi, Andrew Salner, Erik P. Castle, Samira A. Brooks, Miruna Balasundaram, D. Neil Hayes, George Thomas, Eric Chuah, Umadevi Veluvolu, Zhining Wang, Moiz S. Bootwalla, Rebecca Carlsen, Jun Li, Harsha Doddapaneni, Stephen B. Baylin, Eric M. Thompson, Hui Shen, Ying-Bei Chen, Shaowu Meng, Mei Huang, Jodi Harr, John Eckman, Robert Penny, Jia Liu, Laura Dike, Andrew K. Godwin, April DeVolk, Joel S. Parker, Alicia Hawes, Angela N. Brooks, Margi Sheth, Scott M. Haake, Paul M. Weinberger, Satish K. Tickoo, Reanne Bowlby, Kenna R. Mills Shaw, Stuart R. Jefferys, Erin Curley, Donna M. Muzny, Rajiv Dhir, Mark E. Sherman, Kelinda Tucker, Tracie Santos, John N. Weinstein, Kevin Lau, Rehan Akbani, Carl Simon Shelley, Kyle R. Covington, Bogdan Czerniak, Christie Kovar, Todd Pihl, Piotr A. Mieczkowski, Jean C. Zenklusen, Mark Gerstein, Johanna Gardner, William Y. Kim, Marco A. Marra, A. Gordon Robertson, Roy Tarnuzzer, W. Marston Linehan, Lori Huelsenbeck-Dill, Steven J.M. Jones, Hsu Chao, Eve Shinbrot, Somak Roy, Fengju Chen, Pavana Anur, Melissa T. Avedon, Jacqueline E. Schein, Anurag Sethi, Rosemary E. Zuna, James J. Hsieh, Shiyun Ling, Julien Baboud, Robert A. Holt, Suzanne S. Fei, Jay Bowen, Mahmoud Dahdouli, Yunhu Wan, Anil V. Parwani, Stacey Gabriel, Pheroze Tamboli, Jane Zhou, Alan P. Hoyle, Jay Engel, John Bartlett, Michael L. Blute, Peggy Yena, Richard A. Moore, Matthew D. Wilkerson, Christian J. Buhay, Andrew D. Cherniack, Rameen Beroukhim, Michael M. Ittmann, Laurence Albiges, Tara M. Lichtenberg, Julie Bergsten, Carolyn M. Hutter, Ranabir Guin, Yao Fu, Bruce L. Jacobs, Scott Morris, Jennifer Drummond, Brenda Rabeno, Ninad Dewal, Julie M. Gastier-Foster, Myron Peto, Caleb F. Davis, Daniel Crain, Iakovina Alexopoulou, John C. Cheville, Jason Bedford, Ina Felau, Donghui Tan, Liming Yang, David Haussler, Jeff Boyd, Charles M. Perou, Melissa L. Stanton, Ye Wu, Amie Radenbaugh, Paul T. Spellman, Lisle E. Mose, and Jeremy Parfitt
Subjects: 0301 basic medicine, Pathology, medicine.medical_specialty, NF-E2-Related Factor 2, Disease, urologic and male genital diseases, Article, Translational Research, Biomedical, 03 medical and health sciences, 0302 clinical medicine, Renal cell carcinoma, Surveys and Questionnaires, medicine, Carcinoma, Humans, RNA, Messenger, RNA, Neoplasm, Papillary renal cell carcinomas, business.industry, Sequence Analysis, RNA, Cancer, General Medicine, DNA Methylation, Proto-Oncogene Proteins c-met, medicine.disease, Carcinoma, Papillary, Kidney Neoplasms, MicroRNAs, 030104 developmental biology, Phenotype, 030220 oncology & carcinogenesis, Sporadic Papillary Renal Cell Carcinoma, Mutation, Hereditary leiomyomatosis and renal cell carcinoma, CpG Islands, business, Signal Transduction
Abstract: Papillary renal-cell carcinoma, which accounts for 15 to 20% of renal-cell carcinomas, is a heterogeneous disease that consists of various types of renal cancer, including tumors with indolent, multifocal presentation and solitary tumors with an aggressive, highly lethal phenotype. Little is known about the genetic basis of sporadic papillary renal-cell carcinoma, and no effective forms of therapy for advanced disease exist.We performed comprehensive molecular characterization of 161 primary papillary renal-cell carcinomas, using whole-exome sequencing, copy-number analysis, messenger RNA and microRNA sequencing, DNA-methylation analysis, and proteomic analysis.Type 1 and type 2 papillary renal-cell carcinomas were shown to be different types of renal cancer characterized by specific genetic alterations, with type 2 further classified into three individual subgroups on the basis of molecular differences associated with patient survival. Type 1 tumors were associated with MET alterations, whereas type 2 tumors were characterized by CDKN2A silencing, SETD2 mutations, TFE3 fusions, and increased expression of the NRF2-antioxidant response element (ARE) pathway. A CpG island methylator phenotype (CIMP) was observed in a distinct subgroup of type 2 papillary renal-cell carcinomas that was characterized by poor survival and mutation of the gene encoding fumarate hydratase (FH).Type 1 and type 2 papillary renal-cell carcinomas were shown to be clinically and biologically distinct. Alterations in the MET pathway were associated with type 1, and activation of the NRF2-ARE pathway was associated with type 2; CDKN2A loss and CIMP in type 2 conveyed a poor prognosis. Furthermore, type 2 papillary renal-cell carcinoma consisted of at least three subtypes based on molecular and phenotypic features. (Funded by the National Institutes of Health.).
Published: 2015

172. The molecular taxonomy of primary prostate cancer

Author: Piotr A. Mieczkowski, Jianhua Zhang, Saianand Balu, Marc Ladanyi, Victor E. Reuter, Johanna Gardner, Junyuan Wu, Troy Shelton, Simone Chevalier, Marco A. Marra, Anuradha Gopalan, Roy Tarnuzzer, Pei Lin, Joel S. Parker, Umadevi Veluvolu, Lisle E. Mose, Rebecca Carlsen, Michel Carmel, Shalini S. Yadav, Joseph Paulauskis, Fadi Brimo, Sheila Reynolds, Scott Frazer, Natalya Dyakova, Christopher A. Bristow, Brian D. Robinson, Lucie Hamel, Yaron S.N. Butterfield, Yao Fu, Syed Haider, Christopher J. Logothetis, Michael Parfenov, Jeff Boyd, Katherine Tarvin, Kjong-Van Lehmann, Stuart R. Jefferys, Alan P. Hoyle, Arshi Arora, A. Gordon Robertson, Matti Annala, Thomas L. Bauer, Jianhua Luo, Rodolfo Borges Dos Reis, Louis Lacombe, Andrew Salner, Matti Nykter, Alexandre Doueik, Mei Huang, Alireza Moinzadeh, Joshua Armenia, Andre Kahles, Rehan Akbani, Todd Pihl, Gordon Saksena, Robert A. Holt, Felipe Amstalden Trevisan, Mario Berrios, Nina Thiessen, Ronglai Shen, Carrie Sougnez, Xiaojia Ren, Matthew G. Soloway, Lixing Yang, W. Marston Linehan, Chip Stewart, Angeliki Pantazi, Alain Bergeron, Andrea Sboner, Angela Hadjipanayis, Xingzhi Song, Carlos Gilberto Carlotti, Manaswi Gupta, Rashi Naresh, Yiling Lu, Hartmut Juhl, Mark Gerstein, Robert Leung, Sahil Seth, Teri A. Longacre, Ignaty Leshchiner, Chris Sander, Andrew Wei Xu, Anne Marie Mes-Masson, Patrick Teebagy, Julian M. Hess, Matthew Meyerson, Adrian Ally, Jiabin Tang, Ye Wu, Janae V. Simons, David Van Den Berg, Kenna R. Mills Shaw, Patricia Troncoso, Thomas Gribbin, Shannon J. McCall, Andrew K. Godwin, Daniel J. Weisenberger, Kimberly Rieger-Christ, Nilsa C. Ramirez, Peter J. Park, Margi Sheth, Mark E. Sherman, Eric S. Lander, Yunhu Wan, Lisa Iype, Robert Penny, J. Todd Auman, Ekta Khurana, Stephen J. Freedland, Jeffry Simko, Nils Weinhold, Bradley M. Broom, Angela Tam, Nikolaus Schultz, Erik Zmuda, Wei Zhang, Wenyi Wang, Jeffrey Roach, Christopher E. Barbieri, Alan H. Bryce, Qingguo Wang, Lawrence D. True, Christopher C. Benz, Mathieu Latour, Richard A. Moore, Michael Mayo, Yi Zhong, Tara M. Lichtenberg, Jacqueline E. Schein, Svitlana Tyekucheva, Ranabir Guin, Scott L. Carter, Michael Kerger, David Canes, Scott M. Lippman, Alexei Protopopov, Katayoon Kasaian, Peter A. Pinto, Peter S. Nelson, W. Kimryn Rathmell, David Mallery, Brett S. Carver, David I. Heiman, Juok Cho, Doug Voet, Thorsten Schlomm, Janet E. Cowan, Heidi J. Sofia, Peggy Yena, Matthew D. Wilkerson, Glenn Bubley, Tucker W. LeBien, Yan Shi, Lucas Lochovsky, Gordon B. Mills, Hailei Zhang, Andrea Holbrook, Christopher M. Hovens, Christina Yau, Jonathan G. Seidman, Samirkumar B. Amin, Corbin D. Jones, Andrew D. Cherniack, Lori Boice, Laxmi Lolla, Kristen M. Leraas, Denise Brooks, Francesca Demichelis, Maria Christina Tsourlakis, Katherine A. Hoadley, Charles Saller, Leigh B. Thorne, Julie M. Gastier-Foster, Jaegil Kim, Rameen Beroukhim, Peter R. Carroll, John A. Demchok, Christopher J. Kane, Jay Bowen, Massimo Loda, Richard Cartun, Ina Felau, Carl Morrison, Kerstin David, Eliezer M. Van Allen, Laura S. Schmidt, D. Neil Hayes, Adrian Bivol, Michael S. Lawrence, Raju Kucherlapati, Kelsey Zhu, Wen-Bin Liu, Matthew R. Cooperberg, Houtan Noushmehr, Daniel Crain, Luciano Neder, Lynda Chin, Barry S. Taylor, Jiashan Zhang, Bradley A. Murray, Ginette McKercher, Miruna Balasundaram, Chia Chin Wu, Peter T. Scardino, Suhn K. Rhie, Mark A. Rubin, Jean C. Zenklusen, Ronald Simon, Jaeil Ahn, Markus Graefen, Phillip H. Lai, Michael Ittmann, June M. Chan, Maria J. Merino, Andy Chu, Liming Yang, Charles M. Perou, Steven J.M. Jones, Gad Getz, Stacey Gabriel, Martin L. Ferguson, Jianjiong Gao, Payal Sipahimalani, Lisa Wise, Serghei Stepa, Arvind Rao, Bettina F. Drake, Antonia H. Holway, Armaz Mariamidze, Kiley Graim, Juliann Shih, Guido Sauter, Sarah Minner, Amanda Clarke, Harshad S. Mahadeshwar, Andrew J. Mungall, Alain Piché, Cathy D. Vocke, Sudha Chudamani, Yulia Newton, Davide Prandi, Roeland Verhaak, Ilya Shmulevich, Matthew T. Chang, Sara Sadeghi, Michael Button, Joshua M. Stuart, Anne Breggia, Kristian Cibulskis, Giovanni Ciriello, Paul C. Boutros, Yu Chen, Zhining Wang, Jerome Myers, Heidi Dvinge, Ashutosh Tewari, Scott Morris, Andrea Sorcini, Tara Skelly, Niall M. Corcoran, Michael S. Noble, Anthony J. Costello, Timothy C. Thompson, Eric Chuah, Carolyn M. Hutter, Robert K. Bradley, Fred Saad, John A. Libertino, Reanne Bowlby, John A. Stewart, Shiyun Ling, Gunnar Rätsch, George E. Sandusky, Alexis Sharp, Eric J. Burks, Thomas Zeng, Erin Curley, Charlie Sun, Rajiv Dhir, Yussanne Ma, Huihui Ye, Hui Shen, Nils Gehlenborg, Imelda Tenggara, Travis Sullivan, Tom Bodenheimer, Jia Liu, Christopher D. Andry, Adam Abeshouse, Daniela P. Tirapelli, John N. Weinstein, Kevin Lau, Francisco Sanchez-Vega, Armen Aprikian, Peter W. Laird, Noreen Dhalla, Candace Shelton, Joel Nelson, Bernard Têtu, Darlene Lee, Eleonora Scarlata, Mark Nelson, Steven E. Schumacher, Robert J. Klein, Mark Gerken, Donghui Tan, Semin Lee, John S. Witte, Shaowu Meng, Huandong Sun, Moiz S. Bootwalla, Scott A. Tomlins, Institute for Medical Engineering and Science, Broad Institute of MIT and Harvard, Massachusetts Institute of Technology. Department of Biology, Bradley, Robert K, Carmell, Michelle, Carter, Scott, Chin, Lynda, Cibulskis, Kristian, Getz, Gad Asher, Heiman, David, Lander, Eric Steven, Lin, Pei, Loda, Massimo, Meyerson, Matthew L, Park, Peter J, Seidman, Jonathan, Sougnez, Carrie L, Verhaak, Roel, and Voet, Douglas
Subjects: 0301 basic medicine, Oncology, Male, medicine.medical_specialty, DNA Repair, DNA repair, Urology, MEDLINE, Biology, SPOP, Bioinformatics, Molecular taxonomy, General Biochemistry, Genetics and Molecular Biology, Article, Epigenesis, Genetic, Fusion gene, 03 medical and health sciences, Prostate cancer, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, Prostate, Internal medicine, medicine, Humans, Neoplasm Metastasis, Gene, 030304 developmental biology, Gynecology, 0303 health sciences, Primary (chemistry), business.industry, Prostatic Neoplasms, medicine.disease, 3. Good health, Androgen receptor, Gene Expression Regulation, Neoplastic, GENÉTICA, 030104 developmental biology, medicine.anatomical_structure, Receptors, Androgen, 030220 oncology & carcinogenesis, DNA methylation, Mutation, Cancer research, ras Proteins, Gene Fusion, business, Signal Transduction
Abstract: There is substantial heterogeneity among primary prostate cancers, evident in the spectrum of molecular abnormalities and its variable clinical course. As part of The Cancer Genome Atlas (TCGA), we present a comprehensive molecular analysis of 333 primary prostate carcinomas. Our results revealed a molecular taxonomy in which 74% of these tumors fell into one of seven subtypes defined by specific gene fusions (ERG, ETV1/4, and FLI1) or mutations (SPOP, FOXA1, and IDH1). Epigenetic profiles showed substantial heterogeneity, including an IDH1 mutant subset with a methylator phenotype. Androgen receptor (AR) activity varied widely and in a subtype-specific manner, with SPOP and FOXA1 mutant tumors having the highest levels of AR-induced transcripts. 25% of the prostate cancers had a presumed actionable lesion in the PI3K or MAPK signaling pathways, and DNA repair genes were inactivated in 19%. Our analysis reveals molecular heterogeneity among primary prostate cancers, as well as potentially actionable molecular defects., National Institutes of Health (U.S.). (grant 5U24CA143799), National Institutes of Health (U.S.). (grant 5U24CA143835), National Institutes of Health (U.S.). (grant 5U24CA143840), National Institutes of Health (U.S.). (grant 5U24CA143843), National Institutes of Health (U.S.). (grant 5U24CA143845), National Institutes of Health (U.S.). (grant 5U24CA143848), National Institutes of Health (U.S.). (grant 5U24CA143858), National Institutes of Health (U.S.). (grant 5U24CA143866), National Institutes of Health (U.S.). (grant 5U24CA143867), National Institutes of Health (U.S.). (grant 5U24CA143882), National Institutes of Health (U.S.). (grant 5U24CA143883), National Institutes of Health (U.S.). (grant 5U24CA144025), National Institutes of Health (U.S.). (grant U54HG003067), National Institutes of Health (U.S.). (grant U54HG003079), National Institutes of Health (U.S.). (grant U54HG003273), National Institutes of Health (U.S.). (grant P30CA16672)
Published: 2015

173. Clinical, genomic, and metagenomic characterization of oral tongue squamous cell carcinoma in patients who do not smoke

Author: Ryan, Li, Daniel L, Faden, Carole, Fakhry, Chaz, Langelier, Yuchen, Jiao, Yuxuan, Wang, Matthew D, Wilkerson, Chandra Sekhar, Pedamallu, Matthew, Old, James, Lang, Myriam, Loyo, Sun Mi, Ahn, Marietta, Tan, Zhen, Gooi, Jason, Chan, Jeremy, Richmon, Laura D, Wood, Ralph H, Hruban, Justin, Bishop, William H, Westra, Christine H, Chung, Joseph, Califano, Christine G, Gourin, Chetan, Bettegowda, Matthew, Meyerson, Nickolas, Papadopoulos, Kenneth W, Kinzler, Bert, Vogelstein, Joseph L, DeRisi, Wayne M, Koch, and Nishant, Agrawal
Subjects: Male, squamous cell carcinoma, Databases, Factual, Messenger, Cohort Studies, 2.1 Biological and endogenous factors, Aetiology, Cancer, Incidence, Smoking, oral tongue, DNA, Neoplasm, Genomics, Middle Aged, Prognosis, Tongue Neoplasms, Carcinoma, Squamous Cell, Female, Adult, Clinical Sciences, Risk Assessment, Article, Databases, Age Distribution, Clinical Research, Tobacco, Genetics, Humans, Neoplasm Invasiveness, Genetic Predisposition to Disease, RNA, Messenger, Sex Distribution, Dental/Oral and Craniofacial Disease, Factual, Neoplasm Staging, Retrospective Studies, Tobacco Smoke and Health, Prevention, Carcinoma, DNA, Good Health and Well Being, Squamous Cell, Otorhinolaryngology, Dentistry, Mutation, Neoplasm, RNA, Metagenome, head and neck cancer, next-generation sequencing, Tumor Suppressor Protein p53, Digestive Diseases, nonsmokers
Abstract: BackgroundEvidence suggests the incidence of oral tongue squamous cell carcinoma is increasing in young patients, many who have no history of tobacco use.MethodsWe clinically reviewed 89 patients with oral tongue cancer. Exomic sequencing of tumor DNA from 6 nonsmokers was performed and compared to previously sequenced cases. RNA from 20 tumors was evaluated by massively parallel sequencing to search for potentially oncogenic viruses.ResultsNon-smokers (53 of 89) were younger than smokers (36 of 89; mean, 50.4 vs 61.9 years; p
Published: 2015

174. Genomic Classification of Cutaneous Melanoma

Author: W. Kimryn Rathmell, Lauren E. Haydu, Nils Gehlenborg, David Mallery, Lynn M. Herbert, Hailei Zhang, Darlene Lee, Payal Sipahimalani, Richard A. Scolyer, Jonathan R. Stretch, Amanda Clarke, Sudha Chudamani, Dirk Schadendorf, Jeffrey Roach, Troy Shelton, Kerwin F. Shannon, Kadir C. Akdemir, Alexander J. Lazar, Lixing Yang, D. Murawa, Jingchun Zhu, Michael Mayo, Steven E. Schumacher, Marc Ladanyi, Yiling Lu, Levi A. Garraway, Andrew J. Spillane, Giandomenico Russo, Ian R. Watson, Matthew D. Wilkerson, Mei Huang, Chang Jiun Wu, Pedamallu Chandra Sekhar, Laura Brockway-Lunardi, Wiktoria Maria Suchorska, Michael A. Davies, John M. S. Bartlett, Benjamin Gross, Mark Gerken, Georgy Manikhas, William R. Jeck, Michael Dinikin, Sam Ng, Antje Sucker, Sharon K. Huang, Donghui Tan, Semin Lee, Da Yang, Yardena Samuels, Boris C. Bastian, Katherine A. Hoadley, Kenna R. Mills Shaw, Shaowu Meng, Kunal Rai, Sheila Fisher, Tom Bodenheimer, Robyn P. M. Saw, Joel S. Parker, Victoria Fulidou, Scot Waring, Vesteinn Thorsson, Jacqueline E. Schein, Heidi J. Sofia, Jia Liu, Eric S. Lander, Martin L. Miller, Scott E. Woodman, Yunhu Wan, Olga Voronina, Brenda Ayala, Moiz S. Bootwalla, Rileen Sinha, Yonathan Lissanu Deribe, Yussanne Ma, Gabriel Sica, Matthew Ibbs, Pam Bartlett, Arkadiusz Spychała, Sheila Reynolds, Nikolaus Schultz, Jianhua Zhang, Stephen B. Baylin, Saianand Balu, Jay Bowen, Eran Hodis, Olga Potapova, Lori Boice, Julie M. Gastier-Foster, Singer Ma, Victor G. Prieto, Steven J.M. Jones, Konstantin V. Fedosenko, Rehan Akbani, Todd Pihl, Ruibin Xi, Stergios J. Moschos, Lisa Iype, Robert Penny, Vonn Walter, Peter Hersey, Umadevi Veluvolu, Jiabin Tang, Mark A. Jensen, Aaron Chevalier, Nils Weinhold, Yaron S.N. Butterfield, S. Onur Sumer, Lisle E. Mose, Leslie Cope, Angela Tam, Carmelo Gaudioso, Giovanni Ciriello, Jaegil Kim, Noreen Dhalla, Candace Shelton, Andrzej Mackiewicz, Travis I. Zack, James G. Herman, Lisa Zimmer, Chia Chin Wu, Elena Pagani, Franklin W. Huang, Tanja Davidsen, Stuart R. Jefferys, Andy Chu, Harmanjatinder S. Sekhon, Richard A. Moore, Scott L. Carter, Ludmila Danilova, Peter W. Laird, Nicholas K. Hayward, Julien Baboud, A. Gordon Robertson, Scott Morris, Honorata Tatka, Gordon Saksena, Robert A. Holt, Angela Hadjipanayis, Jakub Brzezinski, Lihua Zou, Nilsa C. Ramirez, Witold Kycler, Yasin Senbabaoglu, Xingzhi Song, Barbara Tabak, Christopher C. Benz, Michael Dubina, Wei Zhang, Sophie Egea, Fedor Moiseenko, Marcus Bosenberg, Piotr A. Mieczkowski, Michael J. Quinn, Harindra Arachchi, Andrew J. Mungall, Lynn Cherney, Suresh Ramalingam, Christopher A. Bristow, Hojabr Kakavand, Chris Sander, Peiling Tsou, Anil Korkut, Alan P. Hoyle, Arshi Arora, Kenneth K. Lee, Netty Santoso, Raymond J. Cho, Ricardo Ramirez, Melissa Saul, Haiyan I. Li, Jeremy Parfitt, Valerie Jakrot, Tiffany L. Calderone, Jessica Frick, John N. Weinstein, Brady Bernard, John M. Kirkwood, Dave S.B. Hoon, Carolyn J. Shiau, Carmen Gomez-Fernandez, Michael Krauthammer, Carrie Sougnez, George E. Sandusky, Xiaojia Ren, Charles Schwallier, Carolyn M. Hutter, Radoslaw Łaźniak, Dmitry Belyaev, Richard F. Kefford, Jeffrey M. Trent, Ouida Liu, J. Stephen Ebrom, Yoon La Choi, Maciej Wiznerowicz, Ranabir Guin, Yan Shi, Ewa Leporowska, Zhenlin Ju, Charles Saller, Hyojin Kang, Jean C. Zenklusen, Tony Gutschner, Peter White, Luigi Nezi, Oxana Paklina, Harshad S. Mahadeshwar, Wiam Bshara, Roeland Verhaak, Kenneth Y. Tsai, Ilya Shmulevich, Kristian Cibulskis, Jonathan G. Seidman, Corbin D. Jones, Ayush T. Raman, D. Neil Hayes, Nandita Barnabas, Uma Rao, Jennifer Eschbacher, Timothy R. Fennell, Jeffrey E. Lee, Matthew Meyerson, Jeffrey E. Gershenwald, Elizabeth Buda, Xiaobei Zhao, Jason Roszik, M. Teresiak, Daniel DiCara, Pei Lin, Eliezer M. Van Allen, Scott Frazer, Genevieve M. Boland, Zhining Wang, Susan Hoppough, Konstanty Korski, Michael S. Noble, B. Arman Aksoy, Reanne Bowlby, Adeboye Osunkoya, Taofeek K. Owonikoko, Madhusmita Behera, Shiyun Ling, Erin Curley, Rajiv Dhir, Andrew Wei Xu, David I. Heiman, Samirkumar B. Amin, Andrew D. Cherniack, Brenna Matejka, Rameen Beroukhim, Michael S. Lawrence, Kelsey Zhu, Wen-Bin Liu, Stacey Gabriel, Martin L. Ferguson, Samantha Sharpe, Giannicola Genovese, Jay Engel, Johanna Gardner, Junyuan Wu, Marco A. Marra, Roy Tarnuzzer, John F. Thompson, Denise Brooks, Lawrence N. Kwong, Woong-Yang Park, Daniel J. Weisenberger, J. Todd Auman, Kristen M. Leraas, Margi Sheth, Riccardo Bono, John A. Demchok, Stefania D'Atri, Candace D. Carter, Miruna Balasundaram, Natalie Bir, Matthew G. Soloway, Angeliki Pantazi, Sahil Seth, Qixia A. Deng, Junehawk Lee, Dana Nicholson, Ye Wu, Keith T. Flaherty, Peter J. Park, Amie Radenbaugh, Benjamin Hanf, Katherine Tarvin, James S. Wilmott, Giancarlo Antonini Cappellini, Pawel Murawa, Maria Synott, Jonna Grimsby, Stephen Coons, Joachim Klode, Michael Button, Alyssa Janning, Alexei Protopopov, Florian L. Muller, Donald L. Morton, Joshua M. Stuart, Ina Felau, Cindy Sander, Ruth Halaban, John P. Miller, David Haussler, Monique Albert, Charles M. Perou, Timothy J. Triche, Yichao Sun, Aaron D. Black, Adrian Ally, Sousan Mehrabi, David Van Den Berg, Graham J. Mann, Erik Zmuda, Carl Morrison, Daniel Crain, Douglas Voet, Janae V. Simons, Norman E. Sharpless, Fadlo R. Khuri, Phillip H. Lai, Liming Yang, Anders Jacobsen, Keith A. Delman, Teresa R. Tabler, Gad Getz, Tara M. Lichtenberg, William Lee, Georgina V. Long, Nina Thiessen, Ronglai Shen, Francesca Passarelli, Bradley A. Ozenberger, Gordon B. Mills, Jessica Walton, Greg Eley, Leigh B. Thorne, Merrick I. Ross, Jared Malke, Barry S. Taylor, Juok Cho, William R. Burns, Michael Parfenov, Thomas Gribbin, Yuling Wang, Raju Kucherlapati, Lynda Chin, Bradley A. Murray, Lee Lichtenstein, Jianjiong Gao, and Lisa Wise
Subjects: Skin Neoplasms, Mutant, Medizin, Biology, General Biochemistry, Genetics and Molecular Biology, Subclass, Article, Transcriptome, chemistry.chemical_compound, Databases, Genetic, medicine, Humans, Gene, Melanoma, Genetics, Biochemistry, Genetics and Molecular Biology(all), Cancer, Binimetinib, medicine.disease, National Cancer Institute (U.S.), United States, 3. Good health, chemistry, Cutaneous melanoma, Mutation, Cancer research
Abstract: Summary We describe the landscape of genomic alterations in cutaneous melanomas through DNA, RNA, and protein-based analysis of 333 primary and/or metastatic melanomas from 331 patients. We establish a framework for genomic classification into one of four subtypes based on the pattern of the most prevalent significantly mutated genes: mutant BRAF , mutant RAS , mutant NF1 , and Triple-WT (wild-type). Integrative analysis reveals enrichment of KIT mutations and focal amplifications and complex structural rearrangements as a feature of the Triple-WT subtype. We found no significant outcome correlation with genomic classification, but samples assigned a transcriptomic subclass enriched for immune gene expression associated with lymphocyte infiltrate on pathology review and high LCK protein expression, a T cell marker, were associated with improved patient survival. This clinicopathological and multi-dimensional analysis suggests that the prognosis of melanoma patients with regional metastases is influenced by tumor stroma immunobiology, offering insights to further personalize therapeutic decision-making.
Published: 2015

175. Combined Targeted DNA Sequencing in Non-Small Cell Lung Cancer (NSCLC) Using UNCseq and NGScopy, and RNA Sequencing Using UNCqeR for the Detection of Genetic Aberrations in NSCLC

Author: Joel S. Parker, Michele C. Hayward, Guosheng Zhang, Heejoon Jo, Norman E. Sharpless, Ashley H. Salazar, Karen E. Weck, David A. Eberhard, Marni B. Siegel, Xiaobei Zhao, Margaret L. Gulley, Nirali M. Patel, D. Neil Hayes, Xiaoying Yin, Matthew G. Soloway, Anyou Wang, Matthew D. Wilkerson, Stergios J. Moschos, Vonn Walter, H. Shelton Earp, and Gary B. Rosson
Subjects: Adult, Male, Lung Neoplasms, DNA Copy Number Variations, non-small cell lung cancer (NSCLC), lcsh:Medicine, Genomics, Computational biology, Biology, DNA sequencing, Proto-Oncogene Proteins p21(ras), symbols.namesake, Carcinoma, Non-Small-Cell Lung, medicine, Humans, Genomic library, Copy-number variation, Indel, lcsh:Science, Genetic Association Studies, Aged, Neoplasm Staging, Sanger sequencing, Genetics, Aged, 80 and over, Multidisciplinary, lcsh:R, Computational Biology, Genetic Variation, High-Throughput Nucleotide Sequencing, Reproducibility of Results, Middle Aged, medicine.disease, Mutation, symbols, lcsh:Q, Female, Neoplasm Grading, SNP array, Research Article
Abstract: The recent FDA approval of the MiSeqDx platform provides a unique opportunity to develop targeted next generation sequencing (NGS) panels for human disease, including cancer. We have developed a scalable, targeted panel-based assay termed UNCseq, which involves a NGS panel of over 200 cancer-associated genes and a standardized downstream bioinformatics pipeline for detection of single nucleotide variations (SNV) as well as small insertions and deletions (indel). In addition, we developed a novel algorithm, NGScopy, designed for samples with sparse sequencing coverage to detect large-scale copy number variations (CNV), similar to human SNP Array 6.0 as well as small-scale intragenic CNV. Overall, we applied this assay to 100 snap-frozen lung cancer specimens lacking same-patient germline DNA (07–0120 tissue cohort) and validated our results against Sanger sequencing, SNP Array, and our recently published integrated DNA-seq/RNA-seq assay, UNCqeR, where RNA-seq of same-patient tumor specimens confirmed SNV detected by DNA-seq, if RNA-seq coverage depth was adequate. In addition, we applied the UNCseq assay on an independent lung cancer tumor tissue collection with available same-patient germline DNA (11–1115 tissue cohort) and confirmed mutations using assays performed in a CLIA-certified laboratory. We conclude that UNCseq can identify SNV, indel, and CNV in tumor specimens lacking germline DNA in a cost-efficient fashion.
Published: 2015

176. a genomic-based classification of lung tumors

Author: Clinical Lung Cancer Genome Project, Network Genomic Medicine, Biospecimens, data source sites: Alex Soltermann, Holger Moch, Odd Terje Brustugun, Steinar Solberg, Marius Lund Iversen, Åslaug Helland, Thomas Muley, Hans Hoffmann, Philipp A. Schnabel, Yuan Chen, Harry Groen, Wim Timens, Hannie Sietsma, Joachim H. Clement, Walter Weder, Jörg Sänger, Erich Stoelben, Corinna Ludwig, Walburga Engel Riedel, Egbert Smit, Daniëlle A. M. Heideman, Peter J. F. Snijders, Lucia Nogova, Martin L. Sos, Christian Mattonet, Karin Töpelt, Matthias Scheffler, Eray Goekkurt, Rainer Kappes, Stefan Krüger, Kato Kambartel, Dirk Behringer, Wolfgang Schulte, Wolfgang Galetke, Winfried Randerath, Matthias Heldwein, Andreas Schlesinger, Monika Serke, Khosro Hekmat, Konrad F. Frank, Roland Schnell, Marcel Reiser, Ali Nuri Hünerlitürkoglu, Stephan Schmitz, Lisa Meffert, Yon Dschun Ko, Markus Litt Lampe, Ulrich Gerigk, Rainer Fricke, Benjamin Besse, Christian Brambilla, Sylvie Lantuejoul, Philippe Lorimier, Denis Moro Sibilot, Federico Cappuzzo, Claudia Ligorio, John K. Field, Russell Hyde, Pierre Validire, Philippe Girard, Lucia A. Muscarella, Vito M. Fazio, Michael Hallek, Jean Charles Soria, Scott L. Carter, Gad Getz, D. Neil Hayes, Matthew D. Wilkerson, Viktor Achter, Ulrich Lang, DAMIANI, STEFANIA, Clinical Lung Cancer Genome Project (CLCGP), Network Genomic Medicine (NGM), Biospecimens and data source sites: Alex Soltermann, Holger Moch, Odd Terje Brustugun, Steinar Solberg, Marius Lund-Iversen, Åslaug Helland, Thomas Muley, Hans Hoffmann, Philipp A. Schnabel, Yuan Chen, Harry Groen, Wim Timen, Hannie Sietsma, Joachim H. Clement, Walter Weder, Jörg Sänger, Erich Stoelben, Corinna Ludwig, Walburga Engel-Riedel, Egbert Smit, Daniëlle A. M. Heideman, Peter J. F. Snijder, Lucia Nogova, Martin L. So, Christian Mattonet, Karin Töpelt, Matthias Scheffler, Eray Goekkurt, Rainer Kappe, Stefan Krüger, Kato Kambartel, Dirk Behringer, Wolfgang Schulte, Wolfgang Galetke, Winfried Randerath, Matthias Heldwein, Andreas Schlesinger, Monika Serke, Khosro Hekmat, Konrad F. Frank, Roland Schnell, Marcel Reiser, Ali-Nuri Hünerlitürkoglu, Stephan Schmitz, Lisa Meffert, Yon-Dschun Ko, Markus Litt-Lampe, Ulrich Gerigk, Rainer Fricke, Benjamin Besse, Christian Brambilla, Sylvie Lantuejoul, Philippe Lorimier, Denis Moro-Sibilot, Federico Cappuzzo, Claudia Ligorio, Stefania Damiani, John K. Field, Russell Hyde, Pierre Validire, Philippe Girard, Lucia A. Muscarella, Vito M. Fazio, Michael Hallek, Jean-Charles Soria, Scott L. Carter, Gad Getz, D. Neil Haye, Matthew D. Wilkerson, Viktor Achter, and Ulrich Lang
Subjects: genomics, Lung cancer
Abstract: We characterized genome alterations in 1255 clinically annotated lung tumors of all histological subgroups to identify genetically defined and clinically relevant subtypes. More than 55% of all cases had at least one oncogenic genome alteration potentially amenable to specific therapeutic intervention, including several personalized treatment approaches that are already in clinical evaluation. Marked differences in the pattern of genomic alterations existed between and within histological subtypes, thus challenging the original histomorphological diagnosis. Immunohistochemical studies confirmed many of these reassigned subtypes. The reassignment eliminated almost all cases of large cell carcinomas, some of which had therapeutically relevant alterations. Prospective testing of our genomics-based diagnostic algorithm in 5145 lung cancer patients enabled a genome-based diagnosis in 3863 (75%) patients, confirmed the feasibility of rational reassignments of large cell lung cancer, and led to improvement in overall survival in patients with EGFR-mutant or ALK-rearranged cancers. Thus, our findings provide support for broad implementation of genome-based diagnosis of lung cancer.
Published: 2013

177. The Integrated Genomic Landscape of Thymic Epithelial Tumors

Author: Milan Radovich, Curtis R. Pickering, Ina Felau, Gavin Ha, Hailei Zhang, Heejoon Jo, Katherine A. Hoadley, Pavana Anur, Jiexin Zhang, Mike McLellan, Reanne Bowlby, Thomas Matthew, Ludmila Danilova, Apurva M. Hegde, Jaegil Kim, Mark D.M. Leiserson, Geetika Sethi, Charles Lu, Michael Ryan, Xiaoping Su, Andrew D. Cherniack, Gordon Robertson, Rehan Akbani, Paul Spellman, John N. Weinstein, D. Neil Hayes, Ben Raphael, Tara Lichtenberg, Kristen Leraas, Jean Claude Zenklusen, Junya Fujimoto, Cristovam Scapulatempo-Neto, Andre L. Moreira, David Hwang, James Huang, Mirella Marino, Robert Korst, Giuseppe Giaccone, Yesim Gokmen-Polar, Sunil Badve, Arun Rajan, Philipp Ströbel, Nicolas Girard, Ming S. Tsao, Alexander Marx, Anne S. Tsao, Patrick J. Loehrer, Adrian Ally, Elizabeth L. Appelbaum, J. Todd Auman, Miruna Balasundaram, Saianand Balu, Madhusmita Behera, Rameen Beroukhim, Mario Berrios, Giovanni Blandino, Tom Bodenheimer, Moiz S. Bootwalla, Jay Bowen, Denise Brooks, Flavio M. Carcano, Rebecca Carlsen, Andre L. Carvalho, Patricia Castro, Lara Chalabreysse, Lynda Chin, Juok Cho, Gina Choe, Eric Chuah, Sudha Chudamani, Carrie Cibulskis, Leslie Cope, Matthew G. Cordes, Daniel Crain, Erin Curley, Timothy Defreitas, John A. Demchok, Frank Detterbeck, Noreen Dhalla, Hendrik Dienemann, W. Jeff Edenfield, Francesco Facciolo, Martin L. Ferguson, Scott Frazer, Catrina C. Fronick, Lucinda A. Fulton, Robert S. Fulton, Stacey B. Gabriel, Johanna Gardner, Julie M. Gastier-Foster, Nils Gehlenborg, Mark Gerken, Gad Getz, David I. Heiman, Shital Hobensack, Andrea Holbrook, Robert A. Holt, Alan P. Hoyle, Carolyn M. Hutter, Michael Ittmann, Stuart R. Jefferys, Corbin D. Jones, Steven J.M. Jones, Katayoon Kasaian, Patrick K. Kimes, Phillip H. Lai, Peter W. Laird, Michael S. Lawrence, Pei Lin, Jia Liu, Laxmi Lolla, Yiling Lu, Yussanne Ma, Dennis T. Maglinte, David Mallery, Elaine R. Mardis, Marco A. Marra, Julie Martin, Michael Mayo, Sam Meier, Michael Meister, Shaowu Meng, Matthew Meyerson, Piotr A. Mieczkowski, Christopher A. Miller, Gordon B. Mills, Richard A. Moore, Scott Morris, Lisle E. Mose, Thomas Muley, Andrew J. Mungall, Karen Mungall, Rashi Naresh, Yulia Newton, Michael S. Noble, Taofeek Owonikoko, Joel S. Parker, Joseph Paulaskis, Robert Penny, Charles M. Perou, Corinne Perrin, Todd Pihl, Amie Radenbaugh, Suresh Ramalingam, Nilsa Ramirez, Ralf Rieker, Jeffrey Roach, Sara Sadeghi, Gordon Saksena, Jacqueline E. Schein, Heather K. Schmidt, Steven E. Schumacher, Candace Shelton, Troy Shelton, Yan Shi, Juliann Shih, Gabriel Sica, Henrique C.S. Silveira, Janae V. Simons, Payal Sipahimalani, Tara Skelly, Heidi J. Sofia, Matthew G. Soloway, Joshua Stuart, Qiang Sun, Angela Tam, Donghui Tan, Roy Tarnuzzer, Nina Thiessen, David J. Van Den Berg, Mohammad A. Vasef, Umadevi Veluvolu, Doug Voet, Vonn Walter, Yunhu Wan, Zhining Wang, Arne Warth, Cleo-Aron Weis, Daniel J. Weisenberger, Matthew D. Wilkerson, Lisa Wise, Tina Wong, Hsin-Ta Wu, Ye Wu, Liming Yang, Jiashan Zhang, and Erik Zmuda
Subjects: Adult, Male, 0301 basic medicine, Neuroblastoma RAS viral oncogene homolog, Cancer Research, Thymoma, Adolescent, Biology, medicine.disease_cause, Article, Autoimmunity, Transcription Factors, TFII, Young Adult, 03 medical and health sciences, medicine, Humans, Neoplasms, Glandular and Epithelial, HRAS, Thymic carcinoma, Aged, Aged, 80 and over, Autoimmune disease, Oncogene, Genomics, Thymus Neoplasms, Cell Biology, Middle Aged, medicine.disease, Myasthenia gravis, 3. Good health, 030104 developmental biology, Oncology, Mutation, Cancer research, Female
Abstract: Summary Thymic epithelial tumors (TETs) are one of the rarest adult malignancies. Among TETs, thymoma is the most predominant, characterized by a unique association with autoimmune diseases, followed by thymic carcinoma, which is less common but more clinically aggressive. Using multi-platform omics analyses on 117 TETs, we define four subtypes of these tumors defined by genomic hallmarks and an association with survival and World Health Organization histological subtype. We further demonstrate a marked prevalence of a thymoma-specific mutated oncogene, GTF2I, and explore its biological effects on multi-platform analysis. We further observe enrichment of mutations in HRAS, NRAS, and TP53. Last, we identify a molecular link between thymoma and the autoimmune disease myasthenia gravis, characterized by tumoral overexpression of muscle autoantigens, and increased aneuploidy.
Published: 2018
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178. Comprehensive Molecular Characterization of the Hippo Signaling Pathway in Cancer

Author: Yumeng Wang, Xiaoyan Xu, Dejan Maglic, Michael T. Dill, Kamalika Mojumdar, Patrick Kwok-Shing Ng, Kang Jin Jeong, Yiu Huen Tsang, Daniela Moreno, Venkata Hemanjani Bhavana, Xinxin Peng, Zhongqi Ge, Hu Chen, Jun Li, Zhongyuan Chen, Huiwen Zhang, Leng Han, Di Du, Chad J. Creighton, Gordon B. Mills, Fernando Camargo, Han Liang, Samantha J. Caesar-Johnson, John A. Demchok, Ina Felau, Melpomeni Kasapi, Martin L. Ferguson, Carolyn M. Hutter, Heidi J. Sofia, Roy Tarnuzzer, Zhining Wang, Liming Yang, Jean C. Zenklusen, Jiashan (Julia) Zhang, Sudha Chudamani, Jia Liu, Laxmi Lolla, Rashi Naresh, Todd Pihl, Qiang Sun, Yunhu Wan, Ye Wu, Juok Cho, Timothy DeFreitas, Scott Frazer, Nils Gehlenborg, Gad Getz, David I. Heiman, Jaegil Kim, Michael S. Lawrence, Pei Lin, Sam Meier, Michael S. Noble, Gordon Saksena, Doug Voet, Hailei Zhang, Brady Bernard, Nyasha Chambwe, Varsha Dhankani, Theo Knijnenburg, Roger Kramer, Kalle Leinonen, Yuexin Liu, Michael Miller, Sheila Reynolds, Ilya Shmulevich, Vesteinn Thorsson, Wei Zhang, Rehan Akbani, Bradley M. Broom, Apurva M. Hegde, Zhenlin Ju, Rupa S. Kanchi, Anil Korkut, Shiyun Ling, Wenbin Liu, Yiling Lu, Kwok-Shing Ng, Arvind Rao, Michael Ryan, Jing Wang, John N. Weinstein, Jiexin Zhang, Adam Abeshouse, Joshua Armenia, Debyani Chakravarty, Walid K. Chatila, Ino de Bruijn, Jianjiong Gao, Benjamin E. Gross, Zachary J. Heins, Ritika Kundra, Konnor La, Marc Ladanyi, Augustin Luna, Moriah G. Nissan, Angelica Ochoa, Sarah M. Phillips, Ed Reznik, Francisco Sanchez-Vega, Chris Sander, Nikolaus Schultz, Robert Sheridan, S. Onur Sumer, Yichao Sun, Barry S. Taylor, Jioajiao Wang, Hongxin Zhang, Pavana Anur, Myron Peto, Paul Spellman, Christopher Benz, Joshua M. Stuart, Christopher K. Wong, Christina Yau, D. Neil Hayes, Joel S. Parker, Matthew D. Wilkerson, Adrian Ally, Miruna Balasundaram, Reanne Bowlby, Denise Brooks, Rebecca Carlsen, Eric Chuah, Noreen Dhalla, Robert Holt, Steven J.M. Jones, Katayoon Kasaian, Darlene Lee, Yussanne Ma, Marco A. Marra, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Karen Mungall, A. Gordon Robertson, Sara Sadeghi, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Nina Thiessen, Kane Tse, Tina Wong, Ashton C. Berger, Rameen Beroukhim, Andrew D. Cherniack, Carrie Cibulskis, Stacey B. Gabriel, Galen F. Gao, Gavin Ha, Matthew Meyerson, Steven E. Schumacher, Juliann Shih, Melanie H. Kucherlapati, Raju S. Kucherlapati, Stephen Baylin, Leslie Cope, Ludmila Danilova, Moiz S. Bootwalla, Phillip H. Lai, Dennis T. Maglinte, David J. Van Den Berg, Daniel J. Weisenberger, J. Todd Auman, Saianand Balu, Tom Bodenheimer, Cheng Fan, Katherine A. Hoadley, Alan P. Hoyle, Stuart R. Jefferys, Corbin D. Jones, Shaowu Meng, Piotr A. Mieczkowski, Lisle E. Mose, Amy H. Perou, Charles M. Perou, Jeffrey Roach, Yan Shi, Janae V. Simons, Tara Skelly, Matthew G. Soloway, Donghui Tan, Umadevi Veluvolu, Huihui Fan, Toshinori Hinoue, Peter W. Laird, Hui Shen, Wanding Zhou, Michelle Bellair, Kyle Chang, Kyle Covington, Huyen Dinh, HarshaVardhan Doddapaneni, Lawrence A. Donehower, Jennifer Drummond, Richard A. Gibbs, Robert Glenn, Walker Hale, Yi Han, Jianhong Hu, Viktoriya Korchina, Sandra Lee, Lora Lewis, Wei Li, Xiuping Liu, Margaret Morgan, Donna Morton, Donna Muzny, Jireh Santibanez, Margi Sheth, Eve Shinbrot, Linghua Wang, Min Wang, David A. Wheeler, Liu Xi, Fengmei Zhao, Julian Hess, Elizabeth L. Appelbaum, Matthew Bailey, Matthew G. Cordes, Li Ding, Catrina C. Fronick, Lucinda A. Fulton, Robert S. Fulton, Cyriac Kandoth, Elaine R. Mardis, Michael D. McLellan, Christopher A. Miller, Heather K. Schmidt, Richard K. Wilson, Daniel Crain, Erin Curley, Johanna Gardner, Kevin Lau, David Mallery, Scott Morris, Joseph Paulauskis, Robert Penny, Candace Shelton, Troy Shelton, Mark Sherman, Eric Thompson, Peggy Yena, Jay Bowen, Julie M. Gastier-Foster, Mark Gerken, Kristen M. Leraas, Tara M. Lichtenberg, Nilsa C. Ramirez, Lisa Wise, Erik Zmuda, Niall Corcoran, Tony Costello, Christopher Hovens, Andre L. Carvalho, Ana C. de Carvalho, José H. Fregnani, Adhemar Longatto-Filho, Rui M. Reis, Cristovam Scapulatempo-Neto, Henrique C.S. Silveira, Daniel O. Vidal, Andrew Burnette, Jennifer Eschbacher, Beth Hermes, Ardene Noss, Rosy Singh, Matthew L. Anderson, Patricia D. Castro, Michael Ittmann, David Huntsman, Bernard Kohl, Xuan Le, Richard Thorp, Chris Andry, Elizabeth R. Duffy, Vladimir Lyadov, Oxana Paklina, Galiya Setdikova, Alexey Shabunin, Mikhail Tavobilov, Christopher McPherson, Ronald Warnick, Ross Berkowitz, Daniel Cramer, Colleen Feltmate, Neil Horowitz, Adam Kibel, Michael Muto, Chandrajit P. Raut, Andrei Malykh, Jill S. Barnholtz-Sloan, Wendi Barrett, Karen Devine, Jordonna Fulop, Quinn T. Ostrom, Kristen Shimmel, Yingli Wolinsky, Andrew E. Sloan, Agostino De Rose, Felice Giuliante, Marc Goodman, Beth Y. Karlan, Curt H. Hagedorn, John Eckman, Jodi Harr, Jerome Myers, Kelinda Tucker, Leigh Anne Zach, Brenda Deyarmin, Hai Hu, Leonid Kvecher, Caroline Larson, Richard J. Mural, Stella Somiari, Ales Vicha, Tomas Zelinka, Joseph Bennett, Mary Iacocca, Brenda Rabeno, Patricia Swanson, Mathieu Latour, Louis Lacombe, Bernard Têtu, Alain Bergeron, Mary McGraw, Susan M. Staugaitis, John Chabot, Hanina Hibshoosh, Antonia Sepulveda, Tao Su, Timothy Wang, Olga Potapova, Olga Voronina, Laurence Desjardins, Odette Mariani, Sergio Roman-Roman, Xavier Sastre, Marc-Henri Stern, Feixiong Cheng, Sabina Signoretti, Andrew Berchuck, Darell Bigner, Eric Lipp, Jeffrey Marks, Shannon McCall, Roger McLendon, Angeles Secord, Alexis Sharp, Madhusmita Behera, Daniel J. Brat, Amy Chen, Keith Delman, Seth Force, Fadlo Khuri, Kelly Magliocca, Shishir Maithel, Jeffrey J. Olson, Taofeek Owonikoko, Alan Pickens, Suresh Ramalingam, Dong M. Shin, Gabriel Sica, Erwin G. Van Meir, Hongzheng Zhang, Wil Eijckenboom, Ad Gillis, Esther Korpershoek, Leendert Looijenga, Wolter Oosterhuis, Hans Stoop, Kim E. van Kessel, Ellen C. Zwarthoff, Chiara Calatozzolo, Lucia Cuppini, Stefania Cuzzubbo, Francesco DiMeco, Gaetano Finocchiaro, Luca Mattei, Alessandro Perin, Bianca Pollo, Chu Chen, John Houck, Pawadee Lohavanichbutr, Arndt Hartmann, Christine Stoehr, Robert Stoehr, Helge Taubert, Sven Wach, Bernd Wullich, Witold Kycler, Dawid Murawa, Maciej Wiznerowicz, Ki Chung, W. Jeffrey Edenfield, Julie Martin, Eric Baudin, Glenn Bubley, Raphael Bueno, Assunta De Rienzo, William G. 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Ajani, Ana Maria Angulo Gonzalez, Carmen Behrens, Jolanta Bondaruk, Russell Broaddus, Bogdan Czerniak, Bita Esmaeli, Junya Fujimoto, Jeffrey Gershenwald, Charles Guo, Alexander J. Lazar, Christopher Logothetis, Funda Meric-Bernstam, Cesar Moran, Lois Ramondetta, David Rice, Anil Sood, Pheroze Tamboli, Timothy Thompson, Patricia Troncoso, Anne Tsao, Ignacio Wistuba, Candace Carter, Lauren Haydu, Peter Hersey, Valerie Jakrot, Hojabr Kakavand, Richard Kefford, Kenneth Lee, Georgina Long, Graham Mann, Michael Quinn, Robyn Saw, Richard Scolyer, Kerwin Shannon, Andrew Spillane, Jonathan Stretch, Maria Synott, John Thompson, James Wilmott, Hikmat Al-Ahmadie, Timothy A. Chan, Ronald Ghossein, Anuradha Gopalan, Douglas A. Levine, Victor Reuter, Samuel Singer, Bhuvanesh Singh, Nguyen Viet Tien, Thomas Broudy, Cyrus Mirsaidi, Praveen Nair, Paul Drwiega, Judy Miller, Jennifer Smith, Howard Zaren, Joong-Won Park, Nguyen Phi Hung, Electron Kebebew, W. Marston Linehan, Adam R. 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Subjects: TAZ, 0301 basic medicine, pan-cancer analysis, PROMOTES, Somatic cell, Cancer Genome Atlas Research Network, Protein-Serine-Threonine Kinase, law.invention, law, Neoplasms, LS2_1, LS4_6, TUMOR PROGRESSION, pathway activity, MicroRNA, Prognosis, PANCREATIC-CANCER, 3. Good health, Gene Expression Regulation, Neoplastic, Hippo signaling, ORGAN SIZE CONTROL, GROWTH, YAP, Life Sciences & Biomedicine, pan-cancer analysi, Human, Signal Transduction, animal structures, Prognosi, Computational biology, Biology, Protein Serine-Threonine Kinases, Models, Biological, General Biochemistry, Genetics and Molecular Biology, Article, NO, 03 medical and health sciences, Cell Line, Tumor, GENES SUPRESSORES DE TUMOR, microRNA, BREAST-CANCER, Humans, Hippo Signaling Pathway, Gene, prognostic power, Hippo signaling pathway, Science & Technology, Squamous cell cancer, Base Sequence, driver mutation, Cell Biology, TCGA, GENE, MicroRNAs, 030104 developmental biology, tumor subtype, CELLS, Mutation, miRNA regulation, Neoplasm, Target signature, Suppressor
Abstract: SUMMARY Hippo signaling has been recognized as a key tumor suppressor pathway. Here, we perform a comprehensive molecular characterization of 19 Hippo core genes in 9,125 tumor samples across 33 cancer types using multidimensional “omic” data from The Cancer Genome Atlas. We identify somatic drivers among Hippo genes and the related microRNA (miRNA) regulators, and using functional genomic approaches, we experimentally characterize YAP and TAZ mutation effects and miR-590 and miR-200a regulation for TAZ. Hippo pathway activity is best characterized by a YAP/TAZ transcriptional target signature of 22 genes, which shows robust prognostic power across cancer types. Our elastic-net integrated modeling further reveals cancer-type-specific pathway regulators and associated cancer drivers. Our results highlight the importance of Hippo signaling in squamous cell cancers, characterized by frequent amplification of YAP/TAZ, high expression heterogeneity, and significant prognostic patterns. This study represents a systems-biology approach to characterizing key cancer signaling pathways in the post-genomic era., Graphical Abstract, In Brief Wang et al. perform a comprehensive analysis of 19 Hippo core genes across 33 cancer types using multidimensional “omic” data from The Cancer Genome Atlas. They characterize Hippo pathway activity by a YAP/TAZ transcriptional target signature of 22 genes and highlight the importance of Hippo signaling in squamous cell cancers.
Published: 2018

179. Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas

Author: Theo A. Knijnenburg, Linghua Wang, Michael T. Zimmermann, Nyasha Chambwe, Galen F. Gao, Andrew D. Cherniack, Huihui Fan, Hui Shen, Gregory P. Way, Casey S. Greene, Yuexin Liu, Rehan Akbani, Bin Feng, Lawrence A. Donehower, Chase Miller, Yang Shen, Mostafa Karimi, Haoran Chen, Pora Kim, Peilin Jia, Eve Shinbrot, Shaojun Zhang, Jianfang Liu, Hai Hu, Matthew H. Bailey, Christina Yau, Denise Wolf, Zhongming Zhao, John N. Weinstein, Lei Li, Li Ding, Gordon B. Mills, Peter W. Laird, David A. Wheeler, Ilya Shmulevich, Raymond J. Monnat, Yonghong Xiao, Chen Wang, Samantha J. Caesar-Johnson, John A. Demchok, Ina Felau, Melpomeni Kasapi, Martin L. Ferguson, Carolyn M. Hutter, Heidi J. Sofia, Roy Tarnuzzer, Zhining Wang, Liming Yang, Jean C. Zenklusen, Jiashan (Julia) Zhang, Sudha Chudamani, Jia Liu, Laxmi Lolla, Rashi Naresh, Todd Pihl, Qiang Sun, Yunhu Wan, Ye Wu, Juok Cho, Timothy DeFreitas, Scott Frazer, Nils Gehlenborg, Gad Getz, David I. Heiman, Jaegil Kim, Michael S. Lawrence, Pei Lin, Sam Meier, Michael S. Noble, Gordon Saksena, Doug Voet, Hailei Zhang, Brady Bernard, Varsha Dhankani, Theo Knijnenburg, Roger Kramer, Kalle Leinonen, Michael Miller, Sheila Reynolds, Vesteinn Thorsson, Wei Zhang, Bradley M. Broom, Apurva M. Hegde, Zhenlin Ju, Rupa S. Kanchi, Anil Korkut, Jun Li, Han Liang, Shiyun Ling, Wenbin Liu, Yiling Lu, Kwok-Shing Ng, Arvind Rao, Michael Ryan, Jing Wang, Jiexin Zhang, Adam Abeshouse, Joshua Armenia, Debyani Chakravarty, Walid K. Chatila, Ino de Bruijn, Jianjiong Gao, Benjamin E. Gross, Zachary J. Heins, Ritika Kundra, Konnor La, Marc Ladanyi, Augustin Luna, Moriah G. Nissan, Angelica Ochoa, Sarah M. Phillips, Ed Reznik, Francisco Sanchez-Vega, Chris Sander, Nikolaus Schultz, Robert Sheridan, S. Onur Sumer, Yichao Sun, Barry S. Taylor, Jioajiao Wang, Hongxin Zhang, Pavana Anur, Myron Peto, Paul Spellman, Christopher Benz, Joshua M. Stuart, Christopher K. Wong, D. Neil Hayes, Joel S. Parker, Matthew D. Wilkerson, Adrian Ally, Miruna Balasundaram, Reanne Bowlby, Denise Brooks, Rebecca Carlsen, Eric Chuah, Noreen Dhalla, Robert Holt, Steven J.M. Jones, Katayoon Kasaian, Darlene Lee, Yussanne Ma, Marco A. Marra, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Karen Mungall, A. Gordon Robertson, Sara Sadeghi, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Nina Thiessen, Kane Tse, Tina Wong, Ashton C. Berger, Rameen Beroukhim, Carrie Cibulskis, Stacey B. Gabriel, Gavin Ha, Matthew Meyerson, Steven E. Schumacher, Juliann Shih, Melanie H. Kucherlapati, Raju S. Kucherlapati, Stephen Baylin, Leslie Cope, Ludmila Danilova, Moiz S. Bootwalla, Phillip H. Lai, Dennis T. Maglinte, David J. Van Den Berg, Daniel J. Weisenberger, J. Todd Auman, Saianand Balu, Tom Bodenheimer, Cheng Fan, Katherine A. Hoadley, Alan P. Hoyle, Stuart R. Jefferys, Corbin D. Jones, Shaowu Meng, Piotr A. Mieczkowski, Lisle E. Mose, Amy H. Perou, Charles M. Perou, Jeffrey Roach, Yan Shi, Janae V. Simons, Tara Skelly, Matthew G. Soloway, Donghui Tan, Umadevi Veluvolu, Toshinori Hinoue, Wanding Zhou, Michelle Bellair, Kyle Chang, Kyle Covington, Chad J. Creighton, Huyen Dinh, HarshaVardhan Doddapaneni, Jennifer Drummond, Richard A. Gibbs, Robert Glenn, Walker Hale, Yi Han, Jianhong Hu, Viktoriya Korchina, Sandra Lee, Lora Lewis, Wei Li, Xiuping Liu, Margaret Morgan, Donna Morton, Donna Muzny, Jireh Santibanez, Margi Sheth, Min Wang, Liu Xi, Fengmei Zhao, Julian Hess, Elizabeth L. Appelbaum, Matthew Bailey, Matthew G. Cordes, Catrina C. Fronick, Lucinda A. Fulton, Robert S. Fulton, Cyriac Kandoth, Elaine R. Mardis, Michael D. McLellan, Christopher A. Miller, Heather K. Schmidt, Richard K. Wilson, Daniel Crain, Erin Curley, Johanna Gardner, Kevin Lau, David Mallery, Scott Morris, Joseph Paulauskis, Robert Penny, Candace Shelton, Troy Shelton, Mark Sherman, Eric Thompson, Peggy Yena, Jay Bowen, Julie M. Gastier-Foster, Mark Gerken, Kristen M. Leraas, Tara M. Lichtenberg, Nilsa C. Ramirez, Lisa Wise, Erik Zmuda, Niall Corcoran, Tony Costello, Christopher Hovens, Andre L. Carvalho, Ana C. de Carvalho, José H. Fregnani, Adhemar Longatto-Filho, Rui M. Reis, Cristovam Scapulatempo-Neto, Henrique C.S. Silveira, Daniel O. Vidal, Andrew Burnette, Jennifer Eschbacher, Beth Hermes, Ardene Noss, Rosy Singh, Matthew L. Anderson, Patricia D. Castro, Michael Ittmann, David Huntsman, Bernard Kohl, Xuan Le, Richard Thorp, Chris Andry, Elizabeth R. Duffy, Vladimir Lyadov, Oxana Paklina, Galiya Setdikova, Alexey Shabunin, Mikhail Tavobilov, Christopher McPherson, Ronald Warnick, Ross Berkowitz, Daniel Cramer, Colleen Feltmate, Neil Horowitz, Adam Kibel, Michael Muto, Chandrajit P. Raut, Andrei Malykh, Jill S. Barnholtz-Sloan, Wendi Barrett, Karen Devine, Jordonna Fulop, Quinn T. Ostrom, Kristen Shimmel, Yingli Wolinsky, Andrew E. Sloan, Agostino De Rose, Felice Giuliante, Marc Goodman, Beth Y. Karlan, Curt H. Hagedorn, John Eckman, Jodi Harr, Jerome Myers, Kelinda Tucker, Leigh Anne Zach, Brenda Deyarmin, Leonid Kvecher, Caroline Larson, Richard J. Mural, Stella Somiari, Ales Vicha, Tomas Zelinka, Joseph Bennett, Mary Iacocca, Brenda Rabeno, Patricia Swanson, Mathieu Latour, Louis Lacombe, Bernard Têtu, Alain Bergeron, Mary McGraw, Susan M. Staugaitis, John Chabot, Hanina Hibshoosh, Antonia Sepulveda, Tao Su, Timothy Wang, Olga Potapova, Olga Voronina, Laurence Desjardins, Odette Mariani, Sergio Roman-Roman, Xavier Sastre, Marc-Henri Stern, Feixiong Cheng, Sabina Signoretti, Andrew Berchuck, Darell Bigner, Eric Lipp, Jeffrey Marks, Shannon McCall, Roger McLendon, Angeles Secord, Alexis Sharp, Madhusmita Behera, Daniel J. Brat, Amy Chen, Keith Delman, Seth Force, Fadlo Khuri, Kelly Magliocca, Shishir Maithel, Jeffrey J. Olson, Taofeek Owonikoko, Alan Pickens, Suresh Ramalingam, Dong M. Shin, Gabriel Sica, Erwin G. Van Meir, Hongzheng Zhang, Wil Eijckenboom, Ad Gillis, Esther Korpershoek, Leendert Looijenga, Wolter Oosterhuis, Hans Stoop, Kim E. van Kessel, Ellen C. Zwarthoff, Chiara Calatozzolo, Lucia Cuppini, Stefania Cuzzubbo, Francesco DiMeco, Gaetano Finocchiaro, Luca Mattei, Alessandro Perin, Bianca Pollo, Chu Chen, John Houck, Pawadee Lohavanichbutr, Arndt Hartmann, Christine Stoehr, Robert Stoehr, Helge Taubert, Sven Wach, Bernd Wullich, Witold Kycler, Dawid Murawa, Maciej Wiznerowicz, Ki Chung, W. Jeffrey Edenfield, Julie Martin, Eric Baudin, Glenn Bubley, Raphael Bueno, Assunta De Rienzo, William G. Richards, Steven Kalkanis, Tom Mikkelsen, Houtan Noushmehr, Lisa Scarpace, Nicolas Girard, Marta Aymerich, Elias Campo, Eva Giné, Armando López Guillermo, Nguyen Van Bang, Phan Thi Hanh, Bui Duc Phu, Yufang Tang, Howard Colman, Kimberley Evason, Peter R. Dottino, John A. Martignetti, Hani Gabra, Hartmut Juhl, Teniola Akeredolu, Serghei Stepa, Dave Hoon, Keunsoo Ahn, Koo Jeong Kang, Felix Beuschlein, Anne Breggia, Michael Birrer, Debra Bell, Mitesh Borad, Alan H. Bryce, Erik Castle, Vishal Chandan, John Cheville, John A. Copland, Michael Farnell, Thomas Flotte, Nasra Giama, Thai Ho, Michael Kendrick, Jean-Pierre Kocher, Karla Kopp, Catherine Moser, David Nagorney, Daniel O’Brien, Brian Patrick O’Neill, Tushar Patel, Gloria Petersen, Florencia Que, Michael Rivera, Lewis Roberts, Robert Smallridge, Thomas Smyrk, Melissa Stanton, R. Houston Thompson, Michael Torbenson, Ju Dong Yang, Lizhi Zhang, Fadi Brimo, Jaffer A. Ajani, Ana Maria Angulo Gonzalez, Carmen Behrens, Jolanta Bondaruk, Russell Broaddus, Bogdan Czerniak, Bita Esmaeli, Junya Fujimoto, Jeffrey Gershenwald, Charles Guo, Alexander J. Lazar, Christopher Logothetis, Funda Meric-Bernstam, Cesar Moran, Lois Ramondetta, David Rice, Anil Sood, Pheroze Tamboli, Timothy Thompson, Patricia Troncoso, Anne Tsao, Ignacio Wistuba, Candace Carter, Lauren Haydu, Peter Hersey, Valerie Jakrot, Hojabr Kakavand, Richard Kefford, Kenneth Lee, Georgina Long, Graham Mann, Michael Quinn, Robyn Saw, Richard Scolyer, Kerwin Shannon, Andrew Spillane, Jonathan Stretch, Maria Synott, John Thompson, James Wilmott, Hikmat Al-Ahmadie, Timothy A. Chan, Ronald Ghossein, Anuradha Gopalan, Douglas A. Levine, Victor Reuter, Samuel Singer, Bhuvanesh Singh, Nguyen Viet Tien, Thomas Broudy, Cyrus Mirsaidi, Praveen Nair, Paul Drwiega, Judy Miller, Jennifer Smith, Howard Zaren, Joong-Won Park, Nguyen Phi Hung, Electron Kebebew, W. Marston Linehan, Adam R. Metwalli, Karel Pacak, Peter A. Pinto, Mark Schiffman, Laura S. Schmidt, Cathy D. Vocke, Nicolas Wentzensen, Robert Worrell, Hannah Yang, Marc Moncrieff, Chandra Goparaju, Jonathan Melamed, Harvey Pass, Natalia Botnariuc, Irina Caraman, Mircea Cernat, Inga Chemencedji, Adrian Clipca, Serghei Doruc, Ghenadie Gorincioi, Sergiu Mura, Maria Pirtac, Irina Stancul, Diana Tcaciuc, Monique Albert, Iakovina Alexopoulou, Angel Arnaout, John Bartlett, Jay Engel, Sebastien Gilbert, Jeremy Parfitt, Harman Sekhon, George Thomas, Doris M. Rassl, Robert C. Rintoul, Carlo Bifulco, Raina Tamakawa, Walter Urba, Nicholas Hayward, Henri Timmers, Anna Antenucci, Francesco Facciolo, Gianluca Grazi, Mirella Marino, Roberta Merola, Ronald de Krijger, Anne-Paule Gimenez-Roqueplo, Alain Piché, Simone Chevalier, Ginette McKercher, Kivanc Birsoy, Gene Barnett, Cathy Brewer, Carol Farver, Theresa Naska, Nathan A. Pennell, Daniel Raymond, Cathy Schilero, Kathy Smolenski, Felicia Williams, Carl Morrison, Jeffrey A. Borgia, Michael J. Liptay, Mark Pool, Christopher W. Seder, Kerstin Junker, Larsson Omberg, Mikhail Dinkin, George Manikhas, Domenico Alvaro, Maria Consiglia Bragazzi, Vincenzo Cardinale, Guido Carpino, Eugenio Gaudio, David Chesla, Sandra Cottingham, Michael Dubina, Fedor Moiseenko, Renumathy Dhanasekaran, Karl-Friedrich Becker, Klaus-Peter Janssen, Julia Slotta-Huspenina, Mohamed H. Abdel-Rahman, Dina Aziz, Sue Bell, Colleen M. Cebulla, Amy Davis, Rebecca Duell, J. Bradley Elder, Joe Hilty, Bahavna Kumar, James Lang, Norman L. Lehman, Randy Mandt, Phuong Nguyen, Robert Pilarski, Karan Rai, Lynn Schoenfield, Kelly Senecal, Paul Wakely, Paul Hansen, Ronald Lechan, James Powers, Arthur Tischler, William E. Grizzle, Katherine C. Sexton, Alison Kastl, Joel Henderson, Sima Porten, Jens Waldmann, Martin Fassnacht, Sylvia L. Asa, Dirk Schadendorf, Marta Couce, Markus Graefen, Hartwig Huland, Guido Sauter, Thorsten Schlomm, Ronald Simon, Pierre Tennstedt, Oluwole Olabode, Mark Nelson, Oliver Bathe, Peter R. Carroll, June M. Chan, Philip Disaia, Pat Glenn, Robin K. Kelley, Charles N. Landen, Joanna Phillips, Michael Prados, Jeffry Simko, Karen Smith-McCune, Scott VandenBerg, Kevin Roggin, Ashley Fehrenbach, Ady Kendler, Suzanne Sifri, Ruth Steele, Antonio Jimeno, Francis Carey, Ian Forgie, Massimo Mannelli, Michael Carney, Brenda Hernandez, Benito Campos, Christel Herold-Mende, Christin Jungk, Andreas Unterberg, Andreas von Deimling, Aaron Bossler, Joseph Galbraith, Laura Jacobus, Michael Knudson, Tina Knutson, Deqin Ma, Mohammed Milhem, Rita Sigmund, Andrew K. Godwin, Rashna Madan, Howard G. Rosenthal, Clement Adebamowo, Sally N. Adebamowo, Alex Boussioutas, David Beer, Thomas Giordano, Anne-Marie Mes-Masson, Fred Saad, Therese Bocklage, Lisa Landrum, Robert Mannel, Kathleen Moore, Katherine Moxley, Russel Postier, Joan Walker, Rosemary Zuna, Michael Feldman, Federico Valdivieso, Rajiv Dhir, James Luketich, Edna M. Mora Pinero, Mario Quintero-Aguilo, Carlos Gilberto Carlotti, Jose Sebastião Dos Santos, Rafael Kemp, Ajith Sankarankuty, Daniela Tirapelli, James Catto, Kathy Agnew, Elizabeth Swisher, Jenette Creaney, Bruce Robinson, Carl Simon Shelley, Eryn M. Godwin, Sara Kendall, Cassaundra Shipman, Carol Bradford, Thomas Carey, Andrea Haddad, Jeffey Moyer, Lisa Peterson, Mark Prince, Laura Rozek, Gregory Wolf, Rayleen Bowman, Kwun M. Fong, Ian Yang, Robert Korst, W. Kimryn Rathmell, J. Leigh Fantacone-Campbell, Jeffrey A. Hooke, Albert J. Kovatich, Craig D. Shriver, John DiPersio, Bettina Drake, Ramaswamy Govindan, Sharon Heath, Timothy Ley, Brian Van Tine, Peter Westervelt, Mark A. Rubin, Jung Il Lee, Natália D. Aredes, Armaz Mariamidze, SAIC-F-Frederick, Inc, and Leidos Biomedical Research, Inc.
Subjects: 0301 basic medicine, HUMAN COLON, MICROSATELLITE INSTABILITY, Loss of Heterozygosity, Cancer Genome Atlas Research Network, REPLICATION FORK STABILITY, Genome, Biochemistry, Loss of heterozygosity, Machine Learning, PREDICTS RESPONSE, Neoplasms, DNA damage repair, protein structure analysis, DNA damage footprints, lcsh:QH301-705.5, The Cancer Genome Atlas PanCanAtlas project, epigenetic silencing, integrative statistical analysis, mutational signatures, somatic copy-number alterations, somatic mutations, 3. Good health, INACTIVATION, Life Sciences & Biomedicine, STRUCTURAL BASIS, DNA damage, POLYMERASE-EPSILON, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Cell Line, Tumor, medicine, Gene silencing, Humans, Gene Silencing, Gene, Phenocopy, Science & Technology, MUTANT-CELLS, MUTATIONS, Biochemistry, Genetics and Molecular Biology(all), Genome, Human, Tumor Suppressor Proteins, MUTAÇÃO GENÉTICA, Microsatellite instability, Recombinational DNA Repair, Cell Biology, medicine.disease, body regions, 030104 developmental biology, lcsh:Biology (General), PROMOTER HYPERMETHYLATION, Mutation, Cancer research, Ovarian cancer, Genetics and Molecular Biology(all), DNA Damage
Abstract: SUMMARY DNA damage repair (DDR) pathways modulate cancer risk, progression, and therapeutic response. We systematically analyzed somatic alterations to provide a comprehensive view of DDR deficiency across 33 cancer types. Mutations with accompanying loss of heterozygosity were observed in over 1/3 of DDR genes, including TP53 and BRCA1/2. Other prevalent alterations included epigenetic silencing of the direct repair genes EXO5, MGMT, and ALKBH3 in ~20% of samples. Homologous recombination deficiency (HRD) was present at varying frequency in many cancer types, most notably ovarian cancer. However, in contrast to ovarian cancer, HRD was associated with worse outcomes in several other cancers. Protein structure-based analyses allowed us to predict functional consequences of rare, recurrent DDR mutations. A new machine-learning-based classifier developed from gene expression data allowed us to identify alterations that phenocopy deleterious TP53 mutations. These frequent DDR gene alterations in many human cancers have functional consequences that may determine cancer progression and guide therapy., In Brief Knijnenburg et al. present The Cancer Genome Atlas (TCGA) Pan-Cancer analysis of DNA damage repair (DDR) deficiency in cancer. They use integrative genomic and molecular analyses to identify frequent DDR alterations across 33 cancer types, correlate gene- and pathway-level alterations with genome-wide measures of genome instability and impaired function, and demonstrate the prognostic utility of DDR deficiency scores.
Published: 2018

180. Coexistent ARID1A–PIK3CA mutations promote ovarian clear-cell tumorigenesis through pro-tumorigenic inflammatory cytokine signalling

Author: John P. Didion, Terry Magnuson, Jonathan C. Schisler, David B. Darr, Della Yee, William Y. Kim, Joshua Starmer, Fernando Pardo-Manuel de Villena, Ronald L. Chandler, Daniel W. Serber, Matthew D. Wilkerson, Jeffrey S. Damrauer, Jesse R. Raab, and Jessie Xiong
Subjects: ARID1A, Carcinogenesis, Mutant, General Physics and Astronomy, Haploinsufficiency, medicine.disease_cause, Phosphatidylinositol 3-Kinases, Genes, Tumor Suppressor, Phosphoinositide-3 Kinase Inhibitors, Ovarian Neoplasms, Multidisciplinary, Nuclear Proteins, Ovarian Cancer, 3. Good health, DNA-Binding Proteins, SWI/SNF, Cytokines, Adenocarcinoma, Female, Signal Transduction, Cell Survival, Class I Phosphatidylinositol 3-Kinases, Biology, Article, General Biochemistry, Genetics and Molecular Biology, medicine, Animals, Protein Kinase Inhibitors, Alleles, PI3K/AKT/mTOR pathway, Cell Proliferation, Inflammation, IL-6, Interleukin-6, Cell growth, PIK3CA, General Chemistry, medicine.disease, Survival Analysis, Enzyme Activation, Mice, Inbred C57BL, PI3K pathway, Mutation, Cancer research, Ovarian cancer, Clear cell, Adenocarcinoma, Clear Cell, Transcription Factors
Abstract: Ovarian clear-cell carcinoma (OCCC) is an aggressive form of ovarian cancer with high ARID1A mutation rates. Here we present a mutant mouse model of OCCC. We find that ARID1A inactivation is not sufficient for tumour formation, but requires concurrent activation of the phosphoinositide 3-kinase catalytic subunit, PIK3CA. Remarkably, the mice develop highly penetrant tumours with OCCC-like histopathology, culminating in haemorrhagic ascites and a median survival period of 7.5 weeks. Therapeutic treatment with the pan-PI3K inhibitor, BKM120, prolongs mouse survival by inhibiting the tumour cell growth. Cross-species gene expression comparisons support a role for IL-6 inflammatory cytokine signalling in OCCC pathogenesis. We further show that ARID1A and PIK3CA mutations cooperate to promote tumour growth through sustained IL-6 overproduction. Our findings establish an epistatic relationship between SWI/SNF chromatin remodelling and PI3K pathway mutations in OCCC and demonstrate that these pathways converge on pro-tumorigenic cytokine signalling. We propose that ARID1A protects against inflammation-driven tumorigenesis.
Published: 2015
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181. Comprehensive genomic profiles of small cell lung cancer

Author: Lucia Anna Muscarella, Yong-Hee Kim, Ilona Dahmen, Marc Bos, Luka Ozretić, Dedeepya Vaka, Frauke Leenders, John K. Field, Montserrat Sanchez-Cespedes, Matthew D. Wilkerson, Gavin M. Wright, Sung-Min Chun, Viktor Achter, Lukas C. Heukamp, Danila Seidel, Prudence A. Russell, Peter Nürnberg, Philipp Schaub, Martin Peifer, David Engelmann, Nadine Jahchan, Pierre P. Massion, Roman K. Thomas, Stefan A. Haas, Peter M. Schneider, Elisabeth Brambilla, Julie George, Dian Yang, Maia Segura Wang, Christian Reinhardt, Benjamin Solomon, Anthony N. Karnezis, Koji Tsuta, Roopika Menon, Julien Sage, Dragana Jovanovic, Esmeralda Castaños-Vélez, Takashi Kohno, Ulrich Lang, Helga B. Salvesen, Xin Lu, Ángela Torres, Michael Lindner, Se Jin Jang, Milica Kontic, Hans Hoffmann, Reika Iwakawa, Reinhard Büttner, Berit Pinther, Martin Vingron, Kwon-Sik Park, Sascha Ansén, Yasushi Yatabe, Martin Schuler, Christian Müller, O.T. Brustugun, Jun Yokota, Johan Botling, Neil Hayes, Yupeng Cun, Magdalena Bogus, Deokhoon Kim, Jens Köhler, Jan O. Korbel, William D. Travis, Sebastian Michels, Jürgen Wolf, Martin Sandelin, Marius Lund-Iversen, Brigitte M. Pützer, Verena Tischler, Ina Koch, Ignacija Vlasic, Yuan Chen, Janine Altmüller, Masayuki Noguchi, Michael Hallek, Jing Shan Lim, Alex Soltermann, Lynnette Fernandez-Cuesta, Thomas Zander, Gu Kong, Christian Becker, Luca Roz, Yong Zou, Graziella Bosco, Iver Petersen, Philipp A. Schnabel, Sven Perner, Marko Jakopović, Chang-Min Choi, Jelena Knezevic, Ugo Pastorino, Thomas Muley, Annamaria la Torre, Erik Thunnissen, Pathology, and CCA - Oncogenesis
Subjects: Male, Lung Neoplasms, Medizin, Gene mutation, medicine.disease_cause, Retinoblastoma Protein, Mice, Chromosome Breakpoints, 0302 clinical medicine, Receptors, 2.1 Biological and endogenous factors, Cyclin D1, Aetiology, Lung, Cancer, Genetics, 0303 health sciences, Mutation, Multidisciplinary, Chromothripsis, Tumor, Genome, Receptors, Notch, Lung Cancer, Nuclear Proteins, Genomics, 3. Good health, DNA-Binding Proteins, ASCL1, 030220 oncology & carcinogenesis, Female, Signal Transduction, Human, Notch, General Science & Technology, Comprehensive genomic profiles, Small cell lung cancer, TP53 and RB1 tumor supressors, Notch signaling pathway, Biology, Article, Cell Line, 03 medical and health sciences, Rare Diseases, Cell Line, Tumor, medicine, Animals, Humans, neoplasms, Alleles, 030304 developmental biology, Genome, Human, Animal, Tumor Suppressor Proteins, Gene Expression Profiling, Human Genome, Rovalpituzumab tesirine, Tumor Protein p73, medicine.disease, Neurosecretory Systems, Small Cell Lung Carcinoma, respiratory tract diseases, Gene expression profiling, Disease Models, Animal, Genòmica, Disease Models, Cancer research, Càncer de pulmó, Tumor Suppressor Protein p53
Abstract: We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Deltaex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.
Published: 2015
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182. Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma

Author: Benjamin J. Raphael, Ralph H. Hruban, Andrew J. Aguirre, Richard A. Moffitt, Jen Jen Yeh, Chip Stewart, A. Gordon Robertson, Andrew D. Cherniack, Manaswi Gupta, Gad Getz, Stacey B. Gabriel, Matthew Meyerson, Carrie Cibulskis, Suzanne S. Fei, Toshinori Hinoue, Hui Shen, Peter W. Laird, Shiyun Ling, Yiling Lu, Gordon B. Mills, Rehan Akbani, Phillipe Loher, Eric R. Londin, Isidore Rigoutsos, Aristeidis G. Telonis, Ewan A. Gibb, Anna Goldenberg, Aziz M. Mezlini, Katherine A. Hoadley, Eric Collisson, Eric Lander, Bradley A. Murray, Julian Hess, Mara Rosenberg, Louis Bergelson, Hailei Zhang, Juok Cho, Grace Tiao, Jaegil Kim, Dimitri Livitz, Ignaty Leshchiner, Brendan Reardon, Eliezer Van Allen, Atanas Kamburov, Rameen Beroukhim, Gordon Saksena, Steven E. Schumacher, Michael S. Noble, David I. Heiman, Nils Gehlenborg, Michael S. Lawrence, Volkan Adsay, Gloria Petersen, David Klimstra, Nabeel Bardeesy, Mark D.M. Leiserson, Reanne Bowlby, Katayoon Kasaian, Inanc Birol, Karen L. Mungall, Sara Sadeghi, John N. Weinstein, Paul T. Spellman, Yuexin Liu, Laufey T. Amundadottir, Joel Tepper, Aatur D. Singhi, Rajiv Dhir, Drwiega Paul, Thomas Smyrk, Lizhi Zhang, Paula Kim, Jay Bowen, Jessica Frick, Julie M. Gastier-Foster, Mark Gerken, Kevin Lau, Kristen M. Leraas, Tara M. Lichtenberg, Nilsa C. Ramirez, Jeremy Renkel, Mark Sherman, Lisa Wise, Peggy Yena, Erik Zmuda, Juliann Shih, Adrian Ally, Miruna Balasundaram, Rebecca Carlsen, Andy Chu, Eric Chuah, Amanda Clarke, Noreen Dhalla, Robert A. Holt, Steven J.M. Jones, Darlene Lee, Yussanne Ma, Marco A. Marra, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Nina Thiessen, Kane Tse, Tina Wong, Denise Brooks, J. Todd Auman, Saianand Balu, Tom Bodenheimer, D. Neil Hayes, Alan P. Hoyle, Stuart R. Jefferys, Corbin D. Jones, Shaowu Meng, Piotr A. Mieczkowski, Lisle E. Mose, Charles M. Perou, Amy H. Perou, Jeffrey Roach, Yan Shi, Janae V. Simons, Tara Skelly, Matthew G. Soloway, Donghui Tan, Umadevi Veluvolu, Joel S. Parker, Matthew D. Wilkerson, Anil Korkut, Yasin Senbabaoglu, Patrick Burch, Robert McWilliams, Kari Chaffee, Ann Oberg, Wei Zhang, Marie-Claude Gingras, David A. Wheeler, Liu Xi, Monique Albert, John Bartlett, Harman Sekhon, Yeager Stephen, Zaren Howard, Miller Judy, Anne Breggia, Rachna T. Shroff, Sudha Chudamani, Jia Liu, Laxmi Lolla, Rashi Naresh, Todd Pihl, Qiang Sun, Yunhu Wan, Ye Wu, Smith Jennifer, Kevin Roggin, Karl-Friedrich Becker, Madhusmita Behera, Joseph Bennett, Lori Boice, Eric Burks, Carlos Gilberto Carlotti Junior, John Chabot, Daniela Pretti da Cunha Tirapelli, Jose Sebastião dos Santos, Michael Dubina, Jennifer Eschbacher, Mei Huang, Lori Huelsenbeck-Dill, Roger Jenkins, Alexey Karpov, Rafael Kemp, Vladimir Lyadov, Shishir Maithel, Georgy Manikhas, Eric Montgomery, Houtan Noushmehr, Adeboye Osunkoya, Taofeek Owonikoko, Oxana Paklina, Olga Potapova, Suresh Ramalingam, W. Kimryn Rathmell, Kimberly Rieger-Christ, Charles Saller, Galiya Setdikova, Alexey Shabunin, Gabriel Sica, Tao Su, Travis Sullivan, Pat Swanson, Katherine Tarvin, Michael Tavobilov, Leigh B. Thorne, Stefan Urbanski, Olga Voronina, Timothy Wang, Daniel Crain, Erin Curley, Johanna Gardner, David Mallery, Scott Morris, Joseph Paulauskis, Robert Penny, Candace Shelton, Troy Shelton, Klaus-Peter Janssen, Oliver Bathe, Nathan Bahary, Julia Slotta-Huspenina, Amber Johns, Hanina Hibshoosh, Rosa F. Hwang, Antonia Sepulveda, Amie Radenbaugh, Stephen B. Baylin, Mario Berrios, Moiz S. Bootwalla, Andrea Holbrook, Phillip H. Lai, Dennis T. Maglinte, Swapna Mahurkar, Timothy J. Triche, David J. Van Den Berg, Daniel J. Weisenberger, Lynda Chin, Raju Kucherlapati, Melanie Kucherlapati, Angeliki Pantazi, Peter Park, Doug Voet, Pei Lin, Scott Frazer, Timothy Defreitas, Sam Meier, Sun Young Kwon, Yong Hoon Kim, Sang-Jae Park, Sung-Sik Han, Seong Hoon Kim, Hark Kim, Emma Furth, Margaret Tempero, Chris Sander, Andrew Biankin, David Chang, Peter Bailey, Anthony Gill, James Kench, Sean Grimmond, Australian Pancreatic Cancer Genome Initiative (APGI, Russell Postier, Rosemary Zuna, Hugues Sicotte, John A. Demchok, Martin L. Ferguson, Carolyn M. Hutter, Kenna R. Mills Shaw, Margi Sheth, Heidi J. Sofia, Roy Tarnuzzer, Zhining Wang, Liming Yang, Jiashan (Julia) Zhang, Ina Felau, and Jean C. Zenklusen
Subjects: 0301 basic medicine, Cancer Research, Proteome, endocrine system diseases, ARID1A, medicine.disease_cause, Article, Epigenesis, Genetic, PBRM1, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, CDKN2A, Pancreatic cancer, microRNA, medicine, GNAS complex locus, Humans, neoplasms, biology, Proteomic Profiling, Gene Expression Profiling, ADENOCARCINOMA, Genomics, Cell Biology, DNA Methylation, medicine.disease, digestive system diseases, 3. Good health, Gene Expression Regulation, Neoplastic, Pancreatic Neoplasms, 030104 developmental biology, Oncology, Mutation, Cancer research, biology.protein, KRAS, Transcriptome, Carcinoma, Pancreatic Ductal
Abstract: Summary We performed integrated genomic, transcriptomic, and proteomic profiling of 150 pancreatic ductal adenocarcinoma (PDAC) specimens, including samples with characteristic low neoplastic cellularity. Deep whole-exome sequencing revealed recurrent somatic mutations in KRAS , TP5 3, CDKN2A , SMAD4 , RNF43 , ARID1A , TGFβR2 , GNAS , RREB1 , and PBRM1 . KRAS wild-type tumors harbored alterations in other oncogenic drivers, including GNAS , BRAF , CTNNB1 , and additional RAS pathway genes. A subset of tumors harbored multiple KRAS mutations, with some showing evidence of biallelic mutations. Protein profiling identified a favorable prognosis subset with low epithelial-mesenchymal transition and high MTOR pathway scores. Associations of non-coding RNAs with tumor-specific mRNA subtypes were also identified. Our integrated multi-platform analysis reveals a complex molecular landscape of PDAC and provides a roadmap for precision medicine.
Published: 2017
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183. Abstract 5403: Reproducible elevation of RNA versus DNA mutation signal in low purity breast tumors

Author: Coralie Viollet, Jatinder Singh, Matthew D. Wilkerson, Hai Hu, Jerez Te, Harvey B. Pollard, Craig D. Shriver, Xijun Zhang, Jeffrey A. Hooke, and Clifton L. Dalgard
Subjects: Dna mutation, Cancer Research, Oncology, Elevation, RNA, Biology, Signal, Molecular biology
Abstract: Background: Accurate detection of somatic mutations is critical for informing targeted therapy options. Prevalent non-cancer cell admixture complicates this detection in breast cancer. Conventional mutation detection relies on DNA sequencing; however in prior work, we demonstrated that combining RNA and DNA sequencing increases mutation signal strength, or mutant allele fraction (MAF). The ratio of RNA MAF versus DNA MAF (RNA:DNA MAF) was greatest in low purity breast tumors. We hypothesized that this elevation is biologically driven and would be conserved in a second, distinct tissue specimen of the same tumors. Here, we compare mutation characteristics between two tissue blocks in a cohort of breast tumors (n = 8) to evaluate possible preservation of RNA versus DNA mutation signal throughout the tumor. Methods: We selected four high purity and four low purity breast tumors (“Block1”) from The Cancer Genome Atlas (TCGA) cohort and associated ABSOLUTE purity analysis. For these tumors, we acquired a second tissue block (“Block2”) not analyzed by TCGA, cut sections, analyzed sections by H&E stains, and extracted nucleic acids. Whole genome DNA sequencing and mRNA sequencing was performed for Block2 specimens using Illumina X and NextSeq 500 sequencers, respectively. Somatic mutations in Block2 were detected using UNCeqR and compared to published UNCeqR somatic mutations from TCGA. We then evaluate MAF characteristics in the entire TCGA breast tumor cohort (n = 695). Results: Tumor purity estimates, determined by histology and by sequencing, were reduced in Block2 of the low purity tumor set versus the high purity tumor set, consistent with Block1 analysis. Molecular properties of genome-wide gene expression and somatic DNA copy number were highly similar between block-mated specimens (p < 0.01). We then identified expressed mutations present in Block1 and Block2 of the same tumor and compared the MAFs on these common mutations. DNA MAF and RNA MAF were each significantly correlated between Block1 and Block2 (p < 1e-12 in both cases). The average RNA:DNA MAF was 2.5 for the cohort, indicating that RNA mutation signal is greater than DNA in general. In Block2 specimens, the RNA:DNA MAFs were significantly greater in the low purity tumor set than the high purity tumor set (mean 2.7 versus 2.1, p < 6e-5), reflecting the same trend observed in Block1 specimens. Analyzing the entire TCGA cohort, RNA:DNA MAF was positively correlated with proliferation pathway gene expression (p < 3e-16 ) and was greatest in the Basal subtype versus other subtypes (p < 2e-9). Conclusion: Mutant allele fraction both of DNA and of RNA was conserved across breast tumor subsections. Low purity and basal subtype breast tumors had elevated RNA:DNA MAF supporting a relationship to underlying biology and identifying classes of tumors with pronounced benefit for DNA and RNA integrated mutation analysis. Citation Format: Jerez Te, Coralie Viollet, Xijun Zhang, Jatinder Singh, Jeffrey A. Hooke, Harvey B. Pollard, Hai Hu, Craig D. Shriver, Clifton L. Dalgard, Matthew D. Wilkerson. Reproducible elevation of RNA versus DNA mutation signal in low purity breast tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5403. doi:10.1158/1538-7445.AM2017-5403
Published: 2017
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184. Abstract 4254: Improved understanding of the etiology of breast cancer in young women through evaluation of the genomic landscape

Author: Clifton L. Dalgard, Matthew D. Wilkerson, Craig D. Shriver, and Rachel E. Ellsworth
Subjects: Oncology, APOBEC, Cancer Research, medicine.medical_specialty, business.industry, Disease, medicine.disease, Bioinformatics, Chromosome 17 (human), Breast cancer, Germline mutation, Internal medicine, medicine, Genetic predisposition, DNA mismatch repair, business, CHEK2
Abstract: Background Breast cancer is a disease where biological age and age at menopause are established risk factors, thus diagnosis of breast cancer in young women ( Methods Frozen tumor specimens and matched genomic DNA samples from 31 women diagnosed Results Luminal A tumors from YW had significantly lower somatic mutational loads, copy number alterations and structural variants than other subtypes and structural variants on chromosome 17 were enriched in patients with the HER2-enriched subtype and HER2 status = 3+. Aging was the most common signature (28/31) followed by APOBEC activation (14/31). Signatures associated with defects in mismatch repair (9/31) and polymerase ϵ (10/31) were also detected in >25% of patient tumors. Of the six patients with BRCA defect signatures, three had germline mutations in BRCA2 and one had a CHEK2 mutation. Mutational signatures could cluster patients into two groups, with the youngest patients ( Conclusions Profiling the genome of tumors from YW supports the idea that most tumors are not characterized by profiles associated with genetic predisposition but rather processes such aging, APOBEC activation, mismatch repair, and defects in DNA replication. Of note, breast tumors in the youngest patients ( Citation Format: Matthew D. Wilkerson, Clifton L. Dalgard, Craig D. Shriver, Rachel E. Ellsworth. Improved understanding of the etiology of breast cancer in young women through evaluation of the genomic landscape [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4254. doi:10.1158/1538-7445.AM2017-4254
Published: 2017
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185. Abstract 3259: The genomic landscape of premalignant lung squamous cell carcinoma lesions

Author: Jennifer Beane, Clifton L. Dalgard, Sarah A. Mazzilli, Stefano Monti, Christopher Moy, Marc E. Lenburg, Joshua D. Campbell, Hanqiao Lin, Catalina Perdomo, Gang Liu, Yaron Geshalter, Steven M. Dubinett, Sherry Zhang, Avrum Spira, Matthew Meyerson, Suso Platero, Evan Johnson, Xijun Zhang, Matthew D. Wilkerson, Jessica Vick, Mary E. Reid, and Samjot Singh Dhillon
Subjects: 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, business.industry, Lung squamous cell carcinoma, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, medicine, Cancer research, business
Abstract: Background: Lung squamous cell carcinoma (SqCC) arises in the epithelial layer of the bronchial airway and is often preceded by the development of premalignant lesions. However, not all premalignant lesions progress to lung SqCC and many regress without therapeutic intervention. Understanding the somatic alterations that contribute to progression of premalignant lesions in the airway will allow us to identify biomarkers for early detection and develop therapeutic strategies for early intervention. Methods: Airway biopsies were obtained from high-risk smokers undergoing lung cancer screening by auto-fluorescence bronchoscopy and chest CT at the Roswell Park Cancer Institute. For each subject (n=30), multiple premalignant lesions were sampled repeatedly over time (n=144 samples). One biopsy from each region was sent for pathological review while another biopsy was taken for molecular studies. DNA was also isolated from the blood or cytologically normal bronchial brushings to serve as a matched normal control. Exome capture was performed using the Illumina TruSeq Rapid Exome kit and sequenced to a mean depth of coverage of 120x at Uniform Services University and Walter Reed National Military Medical Center. Results: The median number of somatic mutations across all premalignant lesions was 0.73 per megabase (range: 0.10 - 9.8 per Mb) and displayed a modest association with histological grade (p=0.07). The most frequently mutated lung cancer genes included KMT2C (12%), NOTCH1 (11%), FAT1 (6%), TP53 (5%), and CDKN2A (7/Mb) were taken from adjacent sites over two time points in the same individual with a prior history of lung squamous cell carcinoma. These lesions had a significantly overlapping set of mutations including FAT1 indicating a common evolutionary ancestor. Conclusions: The somatic alterations observed in known cancer genes such as TP53, KMT2C, NOTCH1, and FAT1 may be among the earliest driver events in lung SqCC development and may be useful as biomarkers for early detection as well as targets for lung cancer interception. Citation Format: Joshua Campbell, Xijun Zhang, Samjot S. Dhillon, Catalina Perdomo, Sarah Mazzilli, Yaron Geshalter, Gang Liu, Sherry Zhang, Hanqiao Lin, Jessica Vick, Christopher Moy, Stefano Monti, Evan Johnson, Matthew Meyerson, Steven Dubinett, Suso Platero, Matthew Wilkerson, Clifton Dalgard, Marc Lenburg, Mary Reid, Jennifer Beane, Avrum Spira. The genomic landscape of premalignant lung squamous cell carcinoma lesions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3259. doi:10.1158/1538-7445.AM2017-3259
Published: 2017
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186. Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma

Author: Adrian Ally, Miruna Balasundaram, Rebecca Carlsen, Eric Chuah, Amanda Clarke, Noreen Dhalla, Robert A. Holt, Steven J.M. Jones, Darlene Lee, Yussanne Ma, Marco A. Marra, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Nina Thiessen, Dorothy Cheung, Tina Wong, Denise Brooks, A. Gordon Robertson, Reanne Bowlby, Karen Mungall, Sara Sadeghi, Liu Xi, Kyle Covington, Eve Shinbrot, David A. Wheeler, Richard A. Gibbs, Lawrence A. Donehower, Linghua Wang, Jay Bowen, Julie M. Gastier-Foster, Mark Gerken, Carmen Helsel, Kristen M. Leraas, Tara M. Lichtenberg, Nilsa C. Ramirez, Lisa Wise, Erik Zmuda, Stacey B. Gabriel, Matthew Meyerson, Carrie Cibulskis, Bradley A. Murray, Juliann Shih, Rameen Beroukhim, Andrew D. Cherniack, Steven E. Schumacher, Gordon Saksena, Chandra Sekhar Pedamallu, Lynda Chin, Gad Getz, Michael Noble, Hailei Zhang, David Heiman, Juok Cho, Nils Gehlenborg, Douglas Voet, Pei Lin, Scott Frazer, Timothy Defreitas, Sam Meier, Michael Lawrence, Jaegil Kim, Chad J. Creighton, Donna Muzny, HarshaVardhan Doddapaneni, Jianhong Hu, Min Wang, Donna Morton, Viktoriya Korchina, Yi Han, Huyen Dinh, Lora Lewis, Michelle Bellair, Xiuping Liu, Jireh Santibanez, Robert Glenn, Sandra Lee, Walker Hale, Joel S. Parker, Matthew D. Wilkerson, D. Neil Hayes, Sheila M. Reynolds, Ilya Shmulevich, Wei Zhang, Yuexin Liu, Lisa Iype, Hala Makhlouf, Michael S. Torbenson, Sanjay Kakar, Matthew M. Yeh, Dhanpat Jain, David E. Kleiner, Renumathy Dhanasekaran, Hashem B. El-Serag, Sun Young Yim, John N. Weinstein, Lopa Mishra, Jianping Zhang, Rehan Akbani, Shiyun Ling, Zhenlin Ju, Xiaoping Su, Apurva M. Hegde, Gordon B. Mills, Yiling Lu, Jian Chen, Ju-Seog Lee, Bo Hwa Sohn, Jae Jun Shim, Pan Tong, Hiroyuki Aburatani, Shogo Yamamoto, Kenji Tatsuno, Wei Li, Zheng Xia, Nicolas Stransky, Eric Seiser, Federico Innocenti, Jianjiong Gao, Ritika Kundra, Hongxin Zhang, Zachary Heins, Angelica Ochoa, Chris Sander, Marc Ladanyi, Ronglai Shen, Arshi Arora, Francisco Sanchez-Vega, Nikolaus Schultz, Katayoon Kasaian, Amie Radenbaugh, Karl-Dimiter Bissig, David D. Moore, Yasushi Totoki, Hiromi Nakamura, Tatsuhiro Shibata, Christina Yau, Kiley Graim, Josh Stuart, David Haussler, Betty L. Slagle, Akinyemi I. Ojesina, Panagiotis Katsonis, Amanda Koire, Olivier Lichtarge, Teng-Kuei Hsu, Martin L. Ferguson, John A. Demchok, Ina Felau, Margi Sheth, Roy Tarnuzzer, Zhining Wang, Liming Yang, Jean C. Zenklusen, Jiashan Zhang, Carolyn M. Hutter, Heidi J. Sofia, Roel G.W. Verhaak, Siyuan Zheng, Frederick Lang, Sudha Chudamani, Jia Liu, Laxmi Lolla, Ye Wu, Rashi Naresh, Todd Pihl, Charlie Sun, Yunhu Wan, Christopher Benz, Amy H. Perou, Leigh B. Thorne, Lori Boice, Mei Huang, W. Kimryn Rathmell, Houtan Noushmehr, Fabiano Pinto Saggioro, Daniela Pretti da Cunha Tirapelli, Carlos Gilberto Carlotti Junior, Enio David Mente, Orlando de Castro Silva, Felipe Amstalden Trevisan, Koo Jeong Kang, Keun Soo Ahn, Nasra H. Giama, Catherine D. Moser, Thomas J. Giordano, Michelle Vinco, Theodore H. Welling, Daniel Crain, Erin Curley, Johanna Gardner, David Mallery, Scott Morris, Joseph Paulauskis, Robert Penny, Candace Shelton, Troy Shelton, Robin Kelley, Joong-Won Park, Vishal S. Chandan, Lewis R. Roberts, Oliver F. Bathe, Curt H. Hagedorn, J. Todd Auman, Daniel R. O'Brien, Jean-Pierre A. Kocher, Corbin D. Jones, Piotr A. Mieczkowski, Charles M. Perou, Tara Skelly, Donghui Tan, Umadevi Veluvolu, Saianand Balu, Tom Bodenheimer, Alan P. Hoyle, Stuart R. Jefferys, Shaowu Meng, Lisle E. Mose, Yan Shi, Janae V. Simons, Matthew G. Soloway, Jeffrey Roach, Katherine A. Hoadley, Stephen B. Baylin, Hui Shen, Toshinori Hinoue, Moiz S. Bootwalla, David J. Van Den Berg, Daniel J. Weisenberger, Phillip H. Lai, Andrea Holbrook, Mario Berrios, and Peter W. Laird
Subjects: 0301 basic medicine, Carcinoma, Hepatocellular, Genomics, Biology, medicine.disease_cause, General Biochemistry, Genetics and Molecular Biology, DNA sequencing, 03 medical and health sciences, 0302 clinical medicine, microRNA, medicine, Humans, CARCINOMA HEPATOCELULAR, Gene, Mutation, Liver Neoplasms, DNA Methylation, medicine.disease, Isocitrate Dehydrogenase, MicroRNAs, 030104 developmental biology, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, DNA methylation, Cancer research, Liver cancer
Abstract: Summary Liver cancer has the second highest worldwide cancer mortality rate and has limited therapeutic options. We analyzed 363 hepatocellular carcinoma (HCC) cases by whole-exome sequencing and DNA copy number analyses, and we analyzed 196 HCC cases by DNA methylation, RNA, miRNA, and proteomic expression also. DNA sequencing and mutation analysis identified significantly mutated genes, including LZTR1 , EEF1A1 , SF3B1 , and SMARCA4 . Significant alterations by mutation or downregulation by hypermethylation in genes likely to result in HCC metabolic reprogramming ( ALB , APOB , and CPS1 ) were observed. Integrative molecular HCC subtyping incorporating unsupervised clustering of five data platforms identified three subtypes, one of which was associated with poorer prognosis in three HCC cohorts. Integrated analyses enabled development of a p53 target gene expression signature correlating with poor survival. Potential therapeutic targets for which inhibitors exist include WNT signaling, MDM4, MET, VEGFA, MCL1, IDH1, TERT, and immune checkpoint proteins CTLA-4, PD-1, and PD-L1.
Published: 2017
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187. Characterization of HPV and host genome interactions in primary head and neck cancers

Author: J. Jack Lee, Carter Van Waes, Michael B. Prystowsky, Akinyemi I. Ojesina, Joshua M. Stuart, Mitchell J. Frederick, Angela By Hui, Saianand Balu, Scot Waring, Inanc Birol, Bayardo Perez-Ordonez, Aaron D. Black, Payal Sipahimalani, Wiktoria Maria Suchorska, Michele C. Hayward, Jeffrey Roach, Adrian Ally, Ranabir Guin, Samuel S. Freeman, J. Todd Auman, Hollie A. Harper, Mark E. Prince, David Van Den Berg, Nipun Kakkar, James G. Herman, Adam M. Zanation, Nilsa C. Ramirez, Daniel DiCara, Carol R. Bradford, Paul C. Boutros, Peter W. Laird, Evan G. Taylor, Yan Shi, Jonathan M. Irish, Kristian Cibulskis, Junyuan Wu, Darlene Lee, Katherine A. Hoadley, Jeff Bruce, Yingchun Liu, Heather M. Walline, Carol G. Shores, Raju Kucherlapati, Scott M. Lippman, Colleen Mitchell, Steven E. Schumacher, Wendell G. Yarbrough, Tanguy Y. Seiwert, Sophie C. Egea, Elena Ivanova, Troy Shelton, Jiexin Zhang, Patrick K. Kimes, Nikolaus Schultz, Noreen Dhalla, Maciej Wiznerowicz, Daniel J. Weisenberger, Martin L. Ferguson, Tamara R. Jones, Haiyan I. Li, Nishant Agrawal, Yiling Lu, Lixing Yang, Brandee T. Brown, Julie M. Gastier-Foster, Nils Weinhold, Harshad S. Mahadeshwar, Angela Tam, Lihua Zou, Tom Bodenheimer, Gordon B. Mills, W. Kimryn Rathmell, David Mallery, Semin Lee, Scott J. Morris, Lynn M. Herbert, Hailei Zhang, Thomas C. Motter, Walker Hale, Tina Wong, Yichao Sun, Heidi J. Sofia, Rileen Sinha, Dennis T. Maglinte, Robert I. Haddad, Matthew D. Wilkerson, Jinze Liu, Julien Baboud, Brenda Diergaarde, Michelle Q. Pham, Tanja M. Davidsen, Maureen A. Sartor, Robert A. Holt, Angela Hadjipanayis, Pei Lin, Anders Jacobsen, Stephen C. Benz, Dean Cheng, Matthew Meyerson, Andy Chu, Ezra E.W. Cohen, Joonil Jung, Ari B. Kahn, Scott Frazer, Leigh B. Thorne, Andrew J. Mungall, David A. Wheeler, Nina Thiessen, Jay Bowen, Hui Cheng, D. Neil Hayes, Jennifer Drummond, Patrick Kwok Shing Ng, Harshavardhan Doddapaneni, S. Onur Sumer, Katherine Tarvin, John W.F. Waldron, Nils Gehlenborg, Douglas B. Chepeha, Janae V. Simons, Robert L. Ferris, Paweł Golusiński, Christina Beard, Donna Morton, Boris Reva, Psalm Haseley, Andrew Wei Xu, Giovanni Ciriello, Gregory T. Wolf, Ken Burnett, Lisa A. Peterson, Sylvia Wrenn, Mark A. Jensen, Travis I. Zack, Deepak Srinivasan, Thomas E. Carey, Lisle E. Mose, Mark E. Sherman, Leslie Cope, Adel K. El-Naggar, Marjorie Romkes, D Wheeler, Christopher A. Bristow, Andrea Haddad, Mayya Malakh, Ludmila Danilova, Jean C. Zenklusen, Jiabin Tang, Laura S. Rozek, Jon G. Seidman, Steven J.M. Jones, Hsu Chao, Candance Shelton, Carmen Gomez-Fernandez, Carrie Sougnez, Piotr A. Mieczkowski, Lee Lichtenstein, Erik Zmuda, Johanna Gardner, Jianjiong Gao, Marco A. Marra, Juok Cho, Alexei Protopopov, Roy Tarnuzzer, Tod D. Casasent, Timothy M. Chan, Michael Parfenov, Jing Wang, Christine M. Komarck, Lauren Averett Byers, Rehan Akbani, Todd Pihl, Curtis R. Pickering, Aaron D. Tward, Chandra Sekhar Pedamallu, Han Si, Jan F. Prins, Vonn Walter, Simion I. Chiosea, Jacqueline E. Schein, James Stephen Marron, Ariane Nguyen, William W. Shockley, Jennifer R. Grandis, Zhining Wang, Jeffrey N. Myers, Konstanty Korski, Bradley A. Ozenberger, Margaret L. Gulley, Barry S. Taylor, B. Arman Aksoy, Ni Zhao, Ashley H. Salazar, Petar Stojanov, Tara M. Lichtenberg, Chu Chen, Donghui Tan, Bhishamjit S. Chera, Andrzej Mackiewicz, A. Gordon Robertson, Ronglai Shen, Lisa Wise, Charles M. Perou, Michael Mayo, Charles Saller, Timothy J. Triche, Dong Zeng, Yan Guo, Lixia Diao, Jonathan B. McHugh, Zhixiang Zuo, Gad Getz, John A. Demchok, Raja R. Seethala, Gordon Saksena, Liu Xi, Liming Yang, Justin A. Bishop, Jessica Walton, Greg Eley, Jessica Frick, John N. Weinstein, Kevin Lau, Jianhua Zhang, Kenna R. Mills Shaw, Miruna Balasundaram, Zubair Khan, Umadevi Veluvolu, Stuart R. Jefferys, Christie Kovar, Moiz S. Bootwalla, Rebecca Carlsen, Daniel Crain, Fei-Fei Liu, Matthiew Ibbs, Michael S. Noble, William K. Funkhouser, Shaowu Meng, Mei Huang, Ann Marie Egloff, George E. Sandusky, Yi Han, Eric S. Lander, Sam Ng, William Lee, Christina Yau, Reanne Bowlby, Erin Curley, Donna M. Muzny, Lynda Chin, Joel S. Parker, Stephen B. Baylin, Peter S. Hammerman, Julie Ahn, Christopher C. Benz, Benjamin Gross, Paul M. Weinberger, Gideon Dresdner, Luc G. T. Morris, Zhong Chen, You Hong Fan, Angeliki Pantazi, David I. Heiman, Bartosz Szybiak, Sahil Seth, Richard A. Gibbs, Trevor Hackman, Peggy Yena, Richard A. Moore, Darshan Singh, Yaron S.N. Butterfield, Andrew D. Cherniack, Jeffrey S. Moyer, Robert A. Burton, Peter J. Park, Rameen Beroukhim, Ricardo Ramirez, Natalia Issaeva, Michael S. Lawrence, Wen-Bin Liu, Xiaojia Ren, Chris Sander, Yunhu Wan, Daryl Waggott, Joseph A. Califano, David A. Pot, Mathew G. Soloway, Roni J. Bollag, Stacey Gabriel, Jeffrey S. Reid, Netty Santoso, Elizabeth Buda, Doug Voet, Xingzhi Song, Kyle Chang, Joseph Paulauskis, Thomas M. Harris, Jaegil Kim, Alan P. Hoyle, Marc Ladanyi, Anthony Saleh, Mark C. Weissler, Scott L. Carter, Kai Wang, Jonathan G. Seidman, Corbin D. Jones, Wojciech Golusiński, Robert Penny, Margi Sheth, and Lori Boice
Subjects: Cervical Cancer, Genome, head and neck, Cancer Genome Atlas Network, 2.1 Biological and endogenous factors, 2.2 Factors relating to the physical environment, Papillomaviridae, Aetiology, Genetics, Multidisciplinary, biology, HPV infection, virus diseases, Biological Sciences, integration sites, female genital diseases and pregnancy complications, Gene Expression Regulation, Neoplastic, Infectious Diseases, Head and Neck Neoplasms, DNA methylation, Host-Pathogen Interactions, HIV/AIDS, Infection, Human, Virus Integration, Molecular Sequence Data, DNA sequencing, Rare Diseases, medicine, Humans, cancer, Dental/Oral and Craniofacial Disease, Gene, genome rearrangement, Neoplastic, Base Sequence, Genome, Human, Human Genome, DNA Methylation, biology.organism_classification, medicine.disease, Human genetics, Gene Expression Regulation, Genes, Neoplasm, Sexually Transmitted Infections, Human genome, Genes, Neoplasm, papilloma virus
Abstract: Previous studies have established that a subset of head and neck tumors contains human papillomavirus (HPV) sequences and that HPV-driven head and neck cancers display distinct biological and clinical features. HPV is known to drive cancer by the actions of the E6 and E7 oncoproteins, but the molecular architecture of HPV infection and its interaction with the host genome in head and neck cancers have not been comprehensively described. We profiled a cohort of 279 head and neck cancers with next generation RNA and DNA sequencing and show that 35 (12.5%) tumors displayed evidence of high-risk HPV types 16, 33, or 35. Twenty-five cases had integration of the viral genome into one or more locations in the human genome with statistical enrichment for genic regions. Integrations had a marked impact on the human genome and were associated with alterations in DNA copy number, mRNA transcript abundance and splicing, and both inter- and intrachromosomal rearrangements. Many of these events involved genes with documented roles in cancer. Cancers with integrated vs. nonintegrated HPV displayed different patterns of DNA methylation and both human and viral gene expressions. Together, these data provide insight into the mechanisms by which HPV interacts with the human genome beyond expression of viral oncoproteins and suggest that specific integration events are an integral component of viral oncogenesis.
Published: 2014

188. The Somatic Genomic Landscape of Chromophobe Renal Cell Carcinoma

Author: Caleb F. Davis, Christopher J. Ricketts, Min Wang, Lixing Yang, Andrew D. Cherniack, Hui Shen, Christian Buhay, Hyojin Kang, Sang Cheol Kim, Catherine C. Fahey, Kathryn E. Hacker, Gyan Bhanot, Dmitry A. Gordenin, Andy Chu, Preethi H. Gunaratne, Michael Biehl, Sahil Seth, Benny A. Kaipparettu, Christopher A. Bristow, Lawrence A. Donehower, Eric M. Wallen, Angela B. Smith, Satish K. Tickoo, Pheroze Tamboli, Victor Reuter, Laura S. Schmidt, James J. Hsieh, Toni K. Choueiri, A. Ari Hakimi, Lynda Chin, Matthew Meyerson, Raju Kucherlapati, Woong-Yang Park, A. Gordon Robertson, Peter W. Laird, Elizabeth P. Henske, David J. Kwiatkowski, Peter J. Park, Margaret Morgan, Brian Shuch, Donna Muzny, David A. Wheeler, W. Marston Linehan, Richard A. Gibbs, W. Kimryn Rathmell, Chad J. Creighton, Sabina Signoretti, Christopher Ricketts, Michael Seiler, Hsu Chao, Mike Dahdouli, Liu Xi, Nipun Kakkar, Jeffrey G. Reid, Brittany Downs, Jennifer Drummond, Donna Morton, Harsha Doddapaneni, Lora Lewis, Adam English, Qingchang Meng, Christie Kovar, Qiaoyan Wang, Walker Hale, Alicia Hawes, Divya Kalra, Kimberly Walker, Bradley A. Murray, Carrie Sougnez, Gordon Saksena, Scott L. Carter, Steven E. Schumacher, Barbara Tabak, Travis I. Zack, Gad Getz, Rameen Beroukhim, Stacey B. Gabriel, Adrian Ally, Miruna Balasundaram, Inanc Birol, Denise Brooks, Yaron S.N. Butterfield, Eric Chuah, Amanda Clarke, Noreen Dhalla, Ranabir Guin, Robert A. Holt, Katayoon Kasaian, Darlene Lee, Haiyan I. Li, Emilia Lim, Yussanne Ma, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Nina Thiessen, Tina Wong, Steven J.M. Jones, Marco A. Marra, J. Todd Auman, Donghui Tan, Shaowu Meng, Corbin D. Jones, Katherine A. Hoadley, Piotr A. Mieczkowski, Lisle E. Mose, Stuart R. Jefferys, Jeffrey Roach, Umadevi Veluvolu, Matthew D. Wilkerson, Scot Waring, Elizabeth Buda, Junyuan Wu, Tom Bodenheimer, Alan P. Hoyle, Janae V. Simons, Mathew G. Soloway, Saianand Balu, Joel S. Parker, D. Neil Hayes, Charles M. Perou, Daniel J. Weisenberger, Moiz S. Bootwalla, Timothy Triche, Phillip H. Lai, David J. Van Den Berg, Stephen B. Baylin, Fengju Chen, Cristian Coarfa, Michael S. Noble, Daniel DiCara, Hailei Zhang, Juok Cho, David I. Heiman, Nils Gehlenborg, Doug Voet, Pei Lin, Scott Frazer, Petar Stojanov, Yingchun Liu, Lihua Zou, Jaegil Kim, Michael S. Lawrence, Alexei Protopopov, Xingzhi Song, Jianhua Zhang, Angeliki Pantazi, Angela Hadjipanayis, Eunjung Lee, Lovelace J. Luquette, Semin Lee, Michael Parfenov, Netty Santoso, Jonathan Seidman, Andrew W. Xu, Junehawk Lee, Steven A. Roberts, Leszek J. Klimczak, David Fargo, Martin Lang, Yoon-La Choi, June-Koo Lee, Wenyi Wang, Yu Fan, Jaeil Ahn, Rehan Akbani, John N. Weinstein, David Haussler, Singer Ma, Amie Radenbaugh, Jingchun Zhul, Tara M. Lichtenberg, Erik Zmuda, Aaron D. Black, Benjamin Hanf, Nilsa C. Ramirez, Lisa Wise, Jay Bowen, Kristen M. Leraas, Tracy M. Hall, Julie M. Gastier-Foster, William G. Kaelin, Leigh Thorne, Lori Boice, Mei Huang, Cathy Vocke, James Peterson, Robert Worrell, Maria Merino, Bogdan A. Czerniak, Kenneth D. Aldape, Christopher G. Wood, Paul T. Spellman, Michael B. Atkins, John Cheville, R. Houston Thompson, Mark A. Jensen, Todd Pihl, Yunhu Wan, Brenda Ayala, Julien Baboud, Sudhakar Velaga, Jessica Walton, Jia Liu, Sudha Chudamani, Ye Wu, Margi Sheth, Kenna R. Mills Shaw, John A. Demchok, Tanja Davidsen, Liming Yang, Zhining Wang, Roy W. Tarnuzzer, Jiashan Zhang, Greg Eley, Ina Felau, Jean Claude Zenklusen, Carolyn M. Hutter, Mark S. Guyer, Bradley A. Ozenberger, Heidi J. Sofia, and Intelligent Systems
Subjects: Mitochondrial DNA, Cancer Research, DNA Copy Number Variations, Somatic cell, Chromophobe Renal Cell Carcinoma, DNA Mutational Analysis, Molecular Sequence Data, Chromophobe cell, Biology, DNA, Mitochondrial, Article, Chromosome Breakpoints, Chromosomes, Human, Humans, Exome, Promoter Regions, Genetic, Carcinoma, Renal Cell, Telomerase, Genetics, Base Sequence, Genome, Human, Point mutation, Cell Biology, DNA Methylation, Kidney Neoplasms, Oncology, Kataegis, DNA methylation, Chromosome Deletion, Transcriptome
Abstract: We describe the landscape of somatic genomic alterations of 66 chromophobe renal cell carcinomas (ChRCCs) based on multidimensional and comprehensive characterization, including mitochondrial DNA (mtDNA) and whole genome sequencing. The result is consistent that ChRCC originates from the distal nephron compared to other kidney cancers with more proximal origins. Combined mtDNA and gene expression analysis implicates changes in mitochondrial function as a component of the disease biology, while suggesting alternative roles for mtDNA mutations in cancers relying on oxidative phosphorylation. Genomic rearrangements lead to recurrent structural breakpoints within TERT promoter region, which correlates with highly elevated TERT expression and manifestation of kataegis, representing a mechanism of TERT up-regulation in cancer distinct from previously-observed amplifications and point mutations.
Published: 2014

189. Molecular Subtypes in Head and Neck Cancer Exhibit Distinct Patterns of Chromosomal Gain and Loss of Canonical Cancer Genes

Author: Kenneth L. Muldrew, Mei Kim Ang, Leigh B. Thorne, William D. Funkhouser, Carol G. Shores, Adam M. Zanation, Charles G. Sailey, Mark C. Weissler, Karen J. Fritchie, Michele C. Hayward, Christopher R. Cabanski, Matthew D. Wilkerson, Ying Du, Vonn Walter, Fred A. Wright, William W. Shockley, Xiaoying Yin, Trevor Hackman, Andrew F. Olshan, Scott H. Randell, D. Neil Hayes, Ni Zhao, Ashley H. Salazar, and Katherine A. Hoadley
Subjects: Microarrays, Science, Genetic Causes of Cancer, lcsh:Medicine, Biology, Annotation, Head and Neck Squamous Cell Carcinoma, Genome Analysis Tools, medicine, Chromosomal Gain, Genetics, Cancer Genetics, lcsh:Science, Multidisciplinary, Cancer Risk Factors, Head and neck cancer, lcsh:R, Correction, Computational Biology, Cancers and Neoplasms, Genomics, Genome Scans, medicine.disease, Head and Neck Tumors, Oncology, Cancer gene, Medicine, lcsh:Q, Genome Expression Analysis, Research Article
Abstract: Head and neck squamous cell carcinoma (HNSCC) is a frequently fatal heterogeneous disease. Beyond the role of human papilloma virus (HPV), no validated molecular characterization of the disease has been established. Using an integrated genomic analysis and validation methodology we confirm four molecular classes of HNSCC (basal, mesenchymal, atypical, and classical) consistent with signatures established for squamous carcinoma of the lung, including deregulation of the KEAP1/NFE2L2 oxidative stress pathway, differential utilization of the lineage markers SOX2 and TP63, and preference for the oncogenes PIK3CA and EGFR. For potential clinical use the signatures are complimentary to classification by HPV infection status as well as the putative high risk marker CCND1 copy number gain. A molecular etiology for the subtypes is suggested by statistically significant chromosomal gains and losses and differential cell of origin expression patterns. Model systems representative of each of the four subtypes are also presented.
Published: 2014

190. ABRA: improved coding indel detection via assembly-based realignment

Author: D. Neil Hayes, Charles M. Perou, Lisle E. Mose, Matthew D. Wilkerson, and Joel S. Parker
Subjects: Statistics and Probability, Genotype, Java, Sequence assembly, Computational biology, Biology, Biochemistry, World Wide Web, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, INDEL Mutation, Humans, Indel, Molecular Biology, 030304 developmental biology, computer.programming_language, Supplementary data, 0303 health sciences, Genome, Human, Computational Biology, High-Throughput Nucleotide Sequencing, Sequence Analysis, DNA, Variant allele, Applications Notes, Computer Science Applications, Computational Mathematics, Computational Theory and Mathematics, 030220 oncology & carcinogenesis, Programming Languages, Human genome, Sequence Analysis, Sequence Alignment, computer, Algorithms, Software, Coding (social sciences)
Abstract: Motivation: Variant detection from next-generation sequencing (NGS) data is an increasingly vital aspect of disease diagnosis, treatment and research. Commonly used NGS-variant analysis tools generally rely on accurately mapped short reads to identify somatic variants and germ-line genotypes. Existing NGS read mappers have difficulty accurately mapping short reads containing complex variation (i.e. more than a single base change), thus making identification of such variants difficult or impossible. Insertions and deletions (indels) in particular have been an area of great difficulty. Indels are frequent and can have substantial impact on function, which makes their detection all the more imperative. Results: We present ABRA, an assembly-based realigner, which uses an efficient and flexible localized de novo assembly followed by global realignment to more accurately remap reads. This results in enhanced performance for indel detection as well as improved accuracy in variant allele frequency estimation. Availability and implementation: ABRA is implemented in a combination of Java and C/C++ and is freely available for download at https://github.com/mozack/abra . Contact: lmose@unc.edu ; parkerjs@email.unc.edu Supplementary information: Supplementary data are available at Bioinformatics online.
Published: 2014
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191. The Cancer Genome Atlas Pan-Cancer analysis project

Author: Qunyuan Zhang, B. Arman Aksoy, Fabio Vandin, Eric A. Collisson, Larsson Omberg, S. Onur Sumer, John A. Demchok, Sven Nelander, Vladislav Uzunangelov, Michael C. Wendl, Roger Kramer, John W. Wallis, Brian Craft, Angeliki Pantazi, Leng Han, W. K. Alfred Yung, Brad Ozenberger, Philip L. Lorenzi, James G. Herman, Andy Chu, Sahil Seth, Richard A. Gibbs, Angela Hadjipanayis, Hector Rovira, Peter W. Laird, Inanc Birol, Richard K. Wilson, James Cleland, Peter J. Park, Jiashan Zhang, Payal Sipahimalani, Stanley R. Hamilton, Liming Yang, Seth Lerner, Amie Radenbaugh, Barry S. Taylor, Carrie Hirst, David Tamborero, Stephen B. Baylin, Gad Getz, Tanja Davidsen, Miruna Balasundaram, Cheng Fan, Yuan Yuan, Kristian Cibulskis, Yan Shi, Angela Tam, Divya Kalra, Chris Sander, Scott Abbott, Catrina Fronick, Margi Sheth, Chip Stewart, Angela N. Brooks, Noreen Dhalla, Lam Nguyen, Hui Shen, Travis I. Zack, Andrew J. Mungall, Artem Sokolov, Douglas A. Levine, Carrie Sougnez, Paul T. Spellman, Greg Eley, Deepti Dodda, Wenbin Liu, Michael B. Ryan, Liu Xi, Aaron D. Black, Rong Yao, Saianand Balu, Benjamin P. Berman, Raju Kucherlapati, James M. Melott, Xingzhi Song, Boris Reva, Huyen Dinh, David A. Pot, Michael D. McLellan, Kjong-Van Lehmann, Wenyi Wang, Petar Stojanov, Bradley McIntosh Broom, Timothy J. Ley, Da Yang, Mary Elizabeth Edgerton, Houtan Noushmehr, Mathew G. Soloway, Nina Thiessen, Zhenlin Ju, Mark D.M. Leiserson, Michael Parfenov, Laura van 't Veer, Scott L. Carter, Ludmila Danilova, Adrian Ally, Hailei Zhang, Ina Felau, Carmen Helsel, Kenneth Aldape, Teresia Kling, Charles Lu, Psalm Haseley, A. Gordon Robertson, Andrew Wei Xu, Jessica Frick, Benjamin Gross, Louis M. Staudt, Craig Pohl, Dimitris Anastassiou, Netty Santoso, Donna Muzny, Chad J. Creighton, Donghui Tan, Ryan Bressler, Andrew J. Wong, Barbara Tabak, Yasin Senbabaoglu, Daniel C. Koboldt, Darlene Lee, Doug Voet, Joonil Jung, Hollie A. Harper, Jianhua Zhang, Kyle Chang, Wei Zhao, Marc Ladanyi, Lisa Iype, Ricardo Ramirez, Ami S. Bhatt, Lisle E. Mose, Singer Ma, Abel Gonzalez-Perez, Jonathan G. Seidman, Kosuke Yoshihara, Denise M. Wolf, Corbin D. Jones, Patrik Johansson, Siyuan Zheng, André Kahles, Stacey Gabriel, John N. Weinstein, Han Liang, Samantha Sharpe, Steven E. Schumacher, Matthew Meyerson, D. Neil Hayes, David Haussler, Krishna L. Kanchi, Julie M. Gastier-Foster, Umadevi Veluvolu, Ari B. Kahn, Brady Bernard, Tod D. Casasent, Christopher A. Bristow, Akinyemi I. Ojesina, Sam Ng, Charles M. Perou, Moiz S. Bootwalla, Cyriac Kandoth, Lixing Yang, Joel S. Parker, Alan P. Hoyle, Timothy J. Triche, Dong Zeng, Sean E. McGuire, Christie Kovar, Kim D. Delehaunty, Juok Cho, Alexei Protopopov, Shaowu Meng, Ling Lin, Heather Schmidt, Nils Gehlenborg, Yuexin Liu, Elaine R. Mardis, Martin L. Miller, Jake Lin, Jason Walker, Lisa Wise, Suzanne S. Fei, Jacqueline E. Schein, Semin Lee, Christina Yau, Melisssa Cline, Tara M. Lichtenberg, David I. Heiman, Scot Waring, Richard A. Moore, Margaret B. Morgan, Robert S. Fulton, David E. Larson, Xiaoping Su, Kalle Leinonen, Samirkumar B. Amin, Joshua M. Stuart, J. Todd Auman, Rebecka Jörnsten, Rileen Sinha, Andrew D. Cherniack, Caleb F. Davis, Stephen J. Chanock, Nathan D. Dees, Adam Margolin, Haiyan I. Li, Yaron S.N. Butterfield, Daniel E. Carlin, Tai Hsien Ou Yang, Rameen Beroukhim, Vincent Magrini, Mark P. Hamilton, Grace O. Silva, Nils Weinhold, Harshad S. Mahadeshwar, Michael S. Lawrence, Eric Chuah, Jun Li, Wei Li, Robert A. Burton, Teresa M. Przytycka, Katherine A. Hoadley, Keith A. Baggerly, Sheila M. Reynolds, Daniel DiCara, Tom Bodenheimer, Charles J. Vaske, James M. Eldred, Richard Varhol, Mark A. Jensen, David W. Kane, Xiaojia Ren, Christopher A. Miller, Elizabeth Buda, Li Ding, Michael Mayo, Hsin-Ta Wu, Joelle Kalicki-Veizer, Shelley M. Herbrich, Eunjung Lee, Yingchun Liu, Joshua F. McMichael, Jennifer Drummond, Teresa Swatloski, Harshavardhan Doddapaneni, William Lee, Daniel J. Weisenberger, David A. Wheeler, Chia Chin Wu, Richard Kreisberg, Roeland Verhaak, Elena Helman, Piotr A. Mieczkowski, Mary Goldman, Ilya Shmulevich, Nikolaus Schultz, Min Wang, Lovelace J. Luquette, Marco A. Marra, Todd Pihl, Roy Tarnuzzer, Ronglai Shen, Donna Morton, Yichao Sun, Lawrence A. Donehower, Jun Yao, Theo A. Knijnenburg, Benjamin J. Raphael, Lora Lewis, Peter Waltman, Andrea Eakin, Martin Hirst, Jaegil Kim, Lihua Zou, Ranabir Guin, Yi Han, Scott M. Smith, Hoon Kim, Kristen M. Leraas, Heidi J. Sofia, Erik Zmuda, Matthew D. Wilkerson, Michelle O'Laughlin, Jianjiong Gao, Jeffrey G. Reid, Jing Zhu, Toshinori Hinoue, Gunnar Rätsch, Hye Jung E. Chun, Anders Jacobsen, Stephen C. Benz, Kenna R. Mills Shaw, Gordon B. Mills, Zhining Wang, Cynthia McAllister, Michael S. Noble, Christopher C. Benz, Rehan Akbani, Ruibin Xi, Nianxiang Zhang, Jay Bowen, Wei Zhang, Chandra Sekhar Pedamallu, Eric S. Lander, Yunhu Wan, David J. Dooling, Dong Yeon Cho, Preethi Gunaratne, Todd Wylie, Pei Lin, Chang-Jiun Wu, Jeffrey Roach, Scott Frazer, Samuel S. Freeman, Rachel Abbott, Zheng Xia, Lucinda Fulton, Kyle Ellrott, Nuria Lopez-Bigas, Yang Yang, Michael Miller, Nilsa C. Ramirez, Evan O. Paull, Janae V. Simons, Junyuan Wu, Lynda Chin, Gordon Saksena, Jiabin Tang, Vesteinn Thorsson, Robert A. Holt, Suhn K. Rhie, Steven J.M. Jones, Stuart R. Jeffreys, Giovanni Ciriello, Sofie R. Salama, Gideon Dresdner, Yiling Lu, Massachusetts Institute of Technology. Department of Biology, Lander, Eric S., and Park, Peter J.
Subjects: Genetics, medicine.medical_specialty, Genome, Gene Expression Profiling, Genomics, Computational biology, Biology, Humans, Neoplasms, Article, Analysis Project, Gene expression profiling, GENÉTICA MOLECULAR, Cancer genome, Genomic Profile, medicine, Medical genetics, Epigenetics
Abstract: The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile., National Cancer Institute (U.S.), National Human Genome Research Institute (U.S.)
Published: 2013

192. Comprehensive molecular characterization of urothelial bladder carcinoma

Author: Elizabeth Buda, Nikolaus Schultz, Donghui Tan, Pat Swanson, Xingzhi Song, Jennifer Owens, Carmelo Gaudioso, Liming Yang, Kenna R. Mills Shaw, Sophie C. Egea, John N. Weinstein, Lihua Zou, Dmitry A. Gordenin, Gad Getz, Stuart R. Jefferys, Wiam Bshara, David Haussler, Ari B. Kahn, Mary Iacocca, Brady Bernard, Charles M. Perou, Leigh B. Thorne, Kimberly R. Christ, Eric S. Lander, Yunhu Wan, Timothy J. Triche, Dong Zeng, Bogdan Czerniak, Wenbin Liu, Jianhua Zhang, David Mallery, B. Arman Aksoy, Lynn M. Herbert, Hailei Zhang, Jennifer DiPiero, Tod D. Casasent, Sugy Kodeeswaran, Daniel DiCara, Jacqueline E. Schein, Scott L. Carter, Umadevi Veluvolu, John M. S. Bartlett, Theresa M. Koppie, Ji Yeon Yang, Ronglai Shen, Yingchun Liu, Daniel J. Weisenberger, Ranabir Guin, Myra M. George, Marc Ladanyi, J. Todd Auman, Moiz S. Bootwalla, Shaowu Meng, Mark S. Soloway, Tatjana Antic, Greg Eley, Hikmat Al-Ahmadie, Carolyn M. Hutter, Jonathan G. Seidman, Corbin D. Jones, Lori Boice, Xiaoping Su, Jay Bowen, Raju Kucherlapati, Hui Shen, Benjamin Gross, Reanne Bowlby, Lawrence A. Donehower, Phan Thi Hanh, David J. McConkey, Saianand Balu, Jiexin Zhang, Tina Wong, Juok Cho, Alexei Protopopov, Carolyn L. Smith, Yuexin Liu, Angeliki Pantazi, Jason R. Gee, Xuan Van Le, Ricardo Ramirez, Ami S. Bhatt, Samuel S. Freeman, Jaegil Kim, Bui Duc Phu, Michael Ittman, Charles C. Guo, Carmen Gomez-Fernandez, Norm D. Smith, S. Onur Sumer, Bradley A. Ozenberger, Paul M. Weinberger, George E. Sandusky, Troy Shelton, Seth P. Lerner, Charles Saller, Nicholas J. Petrelli, Nguyen Van Bang, Sahil Seth, Richard A. Gibbs, Lisle E. Mose, Aaron D. Black, Yair Lotan, Carrie Sougnez, Jessie Au, Martin L. Ferguson, Ashley Marie Regazzi, Matthew Meyerson, Joel B. Nelson, Natasja Wye, Daniel E. Carlin, Nils Weinhold, Tom Bodenheimer, Nilsa C. Ramirez, Michael Ryan, Anders Jacobsen, Eric J. Burks, Lee Lichtenstein, Erin Curley, Angela Hadjipanayis, Nils Gehlenborg, Hector Rovira, Bernard Kohl, Jean C. Zenklusen, Travis Sullivan, Margaret Morgan, Rajiv Dhir, Julie M. Gastier-Foster, Gary D. Steinberg, Mathew G. Soloway, Nina Thiessen, Jianjiong Gao, Lisa Wise, Barry S. Taylor, Gordon Saksena, Hui Yao, David Van Den Berg, Jiabin Tang, Robert Penny, Nguyen Viet Tien, Jeffrey R. Gingrich, Jing Zhu, Ronald L. Hrebinko, Dick Kreisberg, Pei Lin, Christopher A. Bristow, Andrey Sivachenko, Andy Chu, Peter W. Laird, Thomas Barr, Junyuan Wu, Robert A. Holt, Harshad S. Mahadeshwar, Piotr A. Mieczkowski, Steven A. Roberts, Victor E. Reuter, Jeffrey S. Damrauer, Roni J. Bollag, Chad J. Creighton, Johanna Gardner, Michael Parfenov, Qiang Li, Phillip H. Lai, Thomas C. Motter, Alireza Moinzadeh, Jodi K. Maranchie, Christopher C. Benz, Lynda Chin, Angela Tam, Margi Sheth, David B. Solit, Erik Zmuda, Lixing Yang, Peter J. Park, Marco A. Marra, Katherine A. Hoadley, Eila C. Skinner, Scott Frazer, Roy Tarnuzzer, Heidi J. Sofia, Bradley M. Broom, Zhining Wang, David I. Heiman, Sebrina A Tello, Lori Huelsenbeck-Dill, Steven J.M. Jones, Antonia H. Holway, Ilana Rebecca Garcia-Grossman, Merce Jorda, Roeland Verhaak, Ilya Shmulevich, W.K. Rathmell, Bernard H. Bochner, Scot Waring, Kenneth Aldape, Richard A. Moore, Toshinori Hinoue, Carrie Hirst, Mark A. Jensen, Payal Kapur, Andrew D. Cherniack, Dean F. Bajorin, Evano Paull, Cheryl M. Lewis, William Y. Kim, Giovanni Ciriello, David C. Fargo, Gordon B. Mills, Michael S. Noble, Stephanie Weaver, Whitney D. McClenden, Benjamin Davies, Payal Sipahimalani, Vina Alexopoulou, Bo Peng, Stephen B. Baylin, Michael Mayo, Rameen Beroukhim, Boris Reva, Anil V. Parwani, Joshua M. Stuart, David J. Kwiatkowski, Stacey B. Gabrie, Janae V. Simons, Rehan Akbani, Todd Pihl, Nianxiang Zhang, Suzie Carter, Michael S. Lawrence, Carmen Helsel, Carl Morrison, Xiaojia Ren, Jeffrey Roach, Peter H. O'Donnell, Miruna Balasundaram, Yevgeniy Antipin, Gideon Dresdner, Cynthia McAllister, Tanja Davidsen, Brenda Rabeno, Jolanta Bondaruk, Kristian Cibulskis, Chip Stewart, Matthew D. Wilkerson, Jonathan E. Rosenberg, Brian D. Robinson, Patricia Castro, Wei Zhang, Chandra Sekhar Pedamallu, Allison Beaver, Andrew Wei Xu, Adrian Ally, Andrea Sorcini, Andrew J. Mungall, Katherine Tarvin, Christine Czerwinski, Petar Stojanov, Philip L. Lorenzi, Alan P. Hoyle, Jay Engel, Tara M. Lichtenberg, D. Neil Hayes, John A. Demchok, Eric Chuah, Benjamin Hanf, Deepak Srinivasan, Donna E. Hansel, Noreen Dhalla, Zhenlin Ju, Leszek J. Klimczak, Trevor J. Pugh, Richard Thorp, A. Gordon Robertson, Darlene Lee, Steven E. Schumacher, Semin Lee, Sheldon I. Bastacky, Rileen Sinha, Haiyan I. Li, William Lee, Sam Ng, Joel S. Parker, Sheila Reynolds, Teresa R. Tabler, Yaron S.N. Butterfield, David Pot, Chris Sander, Wenyi Wang, Weiguo Jian, Le Quang Vinh, Netty Santoso, Doug Voet, and Joonil Jung
Subjects: Metastatic Urothelial Carcinoma, Invasive urothelial carcinoma, Virus Integration, Down-Regulation, Disease, Bioinformatics, Malignancy, Article, Phosphatidylinositol 3-Kinases, Cancer genome, medicine, Carcinoma, Humans, Molecular Targeted Therapy, RNA, Messenger, Urothelial carcinoma, Multidisciplinary, business.industry, TOR Serine-Threonine Kinases, Cell Cycle, Creative commons, medicine.disease, Chromatin, 3. Good health, Gene Expression Regulation, Neoplastic, MicroRNAs, Oxidative Stress, Urinary Bladder Neoplasms, business, Protein Kinases, Proto-Oncogene Proteins c-akt, Signal Transduction
Abstract: Urothelial carcinoma of the bladder is a common malignancy that causes approximately 150,000 deaths per year worldwide. So far, no molecularly targeted agents have been approved for treatment of the disease. As part of The Cancer Genome Atlas project, we report here an integrated analysis of 131 urothelial carcinomas to provide a comprehensive landscape of molecular alterations. There were statistically significant recurrent mutations in 32 genes, including multiple genes involved in cell-cycle regulation, chromatin regulation, and kinase signalling pathways, as well as 9 genes not previously reported as significantly mutated in any cancer. RNA sequencing revealed four expression subtypes, two of which (papillary-like and basal/squamous-like) were also evident in microRNA sequencing and protein data. Whole-genome and RNA sequencing identified recurrent in-frame activating FGFR3-TACC3 fusions and expression or integration of several viruses (including HPV16) that are associated with gene inactivation. Our analyses identified potential therapeutic targets in 69% of the tumours, including 42% with targets in the phosphatidylinositol-3-OH kinase/AKT/mTOR pathway and 45% with targets (including ERBB2) in the RTK/MAPK pathway. Chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any other common cancer studied so far, indicating the future possibility of targeted therapy for chromatin abnormalities.
Published: 2013

193. Comprehensive molecular profiling of lung adenocarcinoma

Author: Amie Radenbaugh, Noreen Dhalla, Christina Williamson, Charles Saller, James Suh, Ramaswamy Govindan, Travis I. Zack, Paul T. Spellman, Daniel DiCara, Harvey I. Pass, Deepak Srinivasan, William G. Richards, Robert J. Cerfolio, Igor Letovanec, A. Gordon Robertson, Gabriel Sica, Chad J. Creighton, Hendrik Dienemann, Jeffrey A. Borgia, Boris Reva, Bryan F. Meyers, Yiling Lu, Nikolaus Schultz, Christopher I. Amos, Dante Trusty, Carmelo Gaudioso, Michael Meister, James T. Robinson, Lihua Zou, James Shin, Jeremy Parfitt, Darlene Lee, Junyuan Wu, Carl Morrison, Scott L. Carter, Giovanni Ciriello, Nils Weinhold, Elena Nemirovich-Danchenko, Andrew Wei Xu, Christopher G. Maher, Lori Boice, Irina Zaytseva, Dennis A. Wigle, Kenna R. Mills Shaw, Matthew G. Soloway, Matthew Meyerson, Peng Chieh Chen, Frank Schneider, Troy Shelton, Douglas Voet, Steven E. Schumacher, D L Rotin, Saianand Balu, Stuart R. Jefferys, Tom Bodenheimer, Bradley A. Ozenberger, Eric S. Lander, Edward Gabrielson, Konstantin V. Fedosenko, Rehan Akbani, William D. Travis, Ari B. Kahn, Marcin Imielinski, Jacqueline E. Schein, Thomas L. Bauer, Kai Ye, Samuel A. Yousem, Robert C. Onofrio, Thomas Muley, Ayesha S. Bryant, Michael K. Asiedu, Monique Albert, Pei Lin, Corbin D. Jones, Edwina Duhig, Jean C. Zenklusen, Lucinda Fulton, Christina Yau, J. Todd Auman, Leigh B. Thorne, Elena Helman, Richard T. Cheney, William Lee, Patrick K. Kimes, Juok Cho, Alexei Protopopov, Wenbin Liu, Lee Lichtenstein, Jing Wang, Lixing Yang, W. Kimryn Rathmell, Jo Ellen Weaver, David A. Wheeler, Leslie Cope, Mark A. Watson, Heidi J. Sofia, Angeliki Pantazi, Ronglai Shen, Jeffrey Roach, Eric A. Collisson, Patrick Kwok Shing Ng, Angela Hadjipanayis, Peter S. Hammerman, David Van Den Berg, Kwun M. Fong, Nils Gehlenborg, Natasha Rekhtman, William K. Funkhouser, D. Neil Hayes, Harshad S. Mahadeshwar, Semin Lee, Martin Peifer, David Mallery, Piotr A. Mieczkowski, Ranabir Guin, Madhusmita Behera, Philipp A. Schnabel, Jill M. Siegfried, Carmen Gomez-Fernandez, Johanna Gardner, Lynn M. Herbert, Hailei Zhang, Robert S. Fulton, Travis Sullivan, Sahil Seth, Sam Ng, Chandra Sekhar Pedamallu, Barry S. Taylor, Venkatraman E. Seshan, Valerie W. Rusch, Jinze Liu, Daniel P. Raymond, Jianjiong Gao, Nathan A. Pennell, Marco A. Marra, Jan F. Prins, Payal Sipahimalani, Janae V. Simons, Joel S. Parker, Rileen Sinha, Lindy Hunter, Raju Kucherlapati, Dennis T. Maglinte, Fedor Moiseenko, Eric E. Snyder, Roy Tarnuzzer, Beverly Lee, James Stephen Marron, Kristian Cibulskis, Jerome Myers, Haiyan I. Li, Robert Penny, Hartmut Juhl, Richard K. Wilson, Zhining Wang, Eran Hodis, Carrie Sougnez, Jiabin Tang, William Mallard, Bryan Hernandez, Liming Yang, Jennifer Brown, Gad Getz, Farhad Kosari, Catrina Fronick, Juliann Chmielecki, Jianhua Zhang, Suresh S. Ramalingam, Michael Parfenov, Peter J. Park, Tanja Davidsen, Philip H. Lai, Jeff Boyd, Dang Huy Quoc Thinh, Harmanjatinder S. Sekhon, Malcolm V. Brock, Mark Pool, Margi Sheth, Kimberly M. Rieger-Christ, Michael J. Liptay, E. Getz, S. Onur Sumer, Ian A. Yang, B. Arman Aksoy, Douglas B. Flieder, Bradley M. Broom, Carrie Hirst, Solange Peters, Joshua M. Stuart, Khurram Z. Khan, Scott Morris, Donghui Tan, Andrew J. Mungall, Ming-Sound Tsao, Gordon B. Mills, Stephen B. Baylin, Rebecca Carlsen, Sanja Dacic, Julien Baboud, Brenda Rabeno, Richard A. Hajek, Lauren Averett Byers, Yaron S.N. Butterfield, Miruna Balasundaram, Chip Stewart, Katherine Tarvin, Peter B. Illei, James G. Herman, David J. Kwiatkowski, Andy Chu, David Haussler, Natasja Wye, Charles M. Perou, Peter W. Laird, Timothy J. Triche, Yan Shi, Jill P. Mesirov, Angela N. Brooks, Lori Huelsenbeck-Dill, Steven J.M. Jones, Antonia H. Holway, Lixia Diao, Anthony A. Gal, David G. Beer, Angela Tam, Ashley H. Salazar, Mark A. Jensen, Robert A. Holt, Katherine A. Hoadley, John A. Demchok, Sandra McDonald, Chandra Goparaju, David Pot, Belinda E. Clarke, Gordon Robertson, Michael C. Wendl, Helga Thorvaldsdottir, Kristen Rogers, Joshua D. Campbell, Chris Sander, Rayleen V. Bowman, Marc Danie Nazaire, Michael Mayo, Olga Voronina, Ludmila Danilova, Paul Zippile, Netty Santoso, John V. Heymach, Matthew D. Wilkerson, John Eckman, Morgan Windsor, Cureline Oleg Dolzhanskiy, Nina Thiessen, Mara Rosenberg, Gideon Dresdner, Levi A. Garraway, Eric Chuah, Richard Varhol, Elizabeth Buda, Li Ding, Alice H. Berger, Xingzhi Song, John M. S. Bartlett, Michael D. McLellan, Olga Potapova, Joseph Paulauskis, Igor Jurisica, Benjamin Gross, Jaegil Kim, John N. Weinstein, Kevin Lau, Christopher R. Cabanski, Philip Bonomi, Michael S. Noble, Maureen F. Zakowski, George E. Sandusky, Mary Iacocca, Eric J. Burks, Erin Curley, Lynda Chin, Rajiv Dhir, Singer Ma, Sophie C. Egea, Umadevi Veluvolu, Sugy Kodeeswaran, Christopher A. Miller, Moiz S. Bootwalla, Daniel J. Weisenberger, Shaowu Meng, Mei Huang, Elaine R. Mardis, Gordon Saksena, Nicholas J. Petrelli, Yvonne Owusu-Sarpong, Christopher C. Benz, Bernard Kohl, Jingchun Zhu, David I. Heiman, Carol Farver, Scot Waring, Richard A. Moore, Darshan Singh, Andrew D. Cherniack, Rameen Beroukhim, Michael S. Lawrence, Xiaojia Ren, Marc Ladanyi, Stacey Gabriel, Christine Czerwinski, Alan P. Hoyle, Cancer Genome Atlas Research Network, Collisson, E. A., Campbell, J.D., Brooks, A.N., Berger, A.H., Lee, W., Chmielecki, J., Beer, D.G., Cope, L., Creighton, C.J., Danilova, L., Ding, L., Getz, G., Hammerman, P.S., Hayes, D.N., Hernandez, B., Herman, J.G., Heymach, J.V., Jurisica, I., Kucherlapati, R., Kwiatkowski, D., Ladanyi, M., Robertson, G., Schultz, N., Shen, R., Sinha, R., Sougnez, C., Tsao, M.S., Travis, W.D., Weinstein, J.N., Wigle, D.A., Wilkerson, M.D., Chu, A., Cherniack, A.D., Hadjipanayis, A., Rosenberg, M., Weisenberger, D.J., Laird, P.W., Radenbaugh, A., Ma, S., Stuart, J.M., Averett Byers, L., Baylin, S.B., Govindan, R., Meyerson, M., Gabriel, S.B., Cibulskis, K., Kim, J., Stewart, C., Lichtenstein, L., Lander, E.S., Lawrence, M.S., Kandoth, C., Fulton, R., Fulton, L.L., McLellan, M.D., Wilson, R.K., Ye, K., Fronick, C.C., Maher, C.A., Miller, C.A., Wendl, M.C., Cabanski, C., Mardis, E., Wheeler, D., Balasundaram, M., Butterfield, Y.S., Carlsen, R., Chuah, E., Dhalla, N., Guin, R., Hirst, C., Lee, D., Li, H.I., Mayo, M., Moore, R.A., Mungall, A.J., Schein, J.E., Sipahimalani, P., Tam, A., Varhol, R., Robertson, A., Wye, N., Thiessen, N., Holt, R.A., Jones, S.J., Marra, M.A., Imielinski, M., Onofrio, R.C., Hodis, E., Zack, T., Helman, E., Sekhar Pedamallu, C., Mesirov, J., Saksena, G., Schumacher, S.E., Carter, S.L., Garraway, L., Beroukhim, R., Lee, S., Mahadeshwar, H.S., Pantazi, A., Protopopov, A., Ren, X., Seth, S., Song, X., Tang, J., Yang, L., Zhang, J., Chen, P.C., Parfenov, M., Wei Xu, A., Santoso, N., Chin, L., Park, P.J., Hoadley, K.A., Auman, J.T., Meng, S., Shi, Y., Buda, E., Waring, S., Veluvolu, U., Tan, D., Mieczkowski, P.A., Jones, C.D., Simons, J.V., Soloway, M.G., Bodenheimer, T., Jefferys, S.R., Roach, J., Hoyle, A.P., Wu, J., Balu, S., Singh, D., Prins, J.F., Marron, J.S., Parker, J.S., Perou, C.M., Liu, J., Maglinte, D.T., Lai, P.H., Bootwalla, M.S., Van Den Berg, D.J., Triche, T., Cho, J., DiCara, D., Heiman, D., Lin, P., Mallard, W., Voet, D., Zhang, H., Zou, L., Noble, M.S., Gehlenborg, N., Thorvaldsdottir, H., Nazaire, M.D., Robinson, J., Aksoy, B.A., Ciriello, G., Taylor, B.S., Dresdner, G., Gao, J., Gross, B., Seshan, V.E., Reva, B., Sumer, S.O., Weinhold, N., Sander, C., Ng, S., Zhu, J., Benz, C.C., Yau, C., Haussler, D., Spellman, P.T., Kimes, P.K., Broom, B.M., Wang, J., Lu, Y., Kwok Shing Ng, P., Diao, L., Liu, W., Amos, C.I., Akbani, R., Mills, G.B., Curley, E., Paulauskis, J., Lau, K., Morris, S., Shelton, T., Mallery, D., Gardner, J., Penny, R., Saller, C., Tarvin, K., Richards, W.G., Cerfolio, R., Bryant, A., Raymond, D.P., Pennell, N.A., Farver, C., Czerwinski, C., Huelsenbeck-Dill, L., Iacocca, M., Petrelli, N., Rabeno, B., Brown, J., Bauer, T., Dolzhanskiy, O., Potapova, O., Rotin, D., Voronina, O., Nemirovich-Danchenko, E., Fedosenko, K.V., Gal, A., Behera, M., Ramalingam, S.S., Sica, G., Flieder, D., Boyd, J., Weaver, J., Kohl, B., Huy Quoc Thinh, D., Sandusky, G., Juhl, H., Duhig, E., Illei, P., Gabrielson, E., Shin, J., Lee, B., Rodgers, K., Trusty, D., Brock, M.V., Williamson, C., Burks, E., Rieger-Christ, K., Holway, A., Sullivan, T., Asiedu, M.K., Kosari, F., Rekhtman, N., Zakowski, M., Rusch, V.W., Zippile, P., Suh, J., Pass, H., Goparaju, C., Owusu-Sarpong, Y., Bartlett, J.M., Kodeeswaran, S., Parfitt, J., Sekhon, H., Albert, M., Eckman, J., Myers, J.B., Cheney, R., Morrison, C., Gaudioso, C., Borgia, J.A., Bonomi, P., Pool, M., Liptay, M.J., Moiseenko, F., Zaytseva, I., Dienemann, H., Meister, M., Schnabel, P.A., Muley, T.R., Peifer, M., Gomez-Fernandez, C., Herbert, L., Egea, S., Huang, M., Thorne, L.B., Boice, L., Hill Salazar, A., Funkhouser, W.K., Rathmell, W.K., Dhir, R., Yousem, S.A., Dacic, S., Schneider, F., Siegfried, J.M., Hajek, R., Watson, M.A., McDonald, S., Meyers, B., Clarke, B., Yang, I.A., Fong, K.M., Hunter, L., Windsor, M., Bowman, R.V., Peters, S., Letovanec, I., Khan, K.Z., Jensen, M.A., Snyder, E.E., Srinivasan, D., Kahn, A.B., Baboud, J., Pot, D.A., Mills Shaw, K.R., Sheth, M., Davidsen, T., Demchok, J.A., Wang, Z., Tarnuzzer, R., Zenklusen, J.C., Ozenberger, B.A., Sofia, H.J., Massachusetts Institute of Technology. Department of Biology, and Lander, Eric S.
Subjects: Male, Lung Neoplasms, Adenocarcinoma/genetics, Adenocarcinoma/pathology, Cell Cycle Proteins/genetics, Female, Gene Dosage, Gene Expression Regulation, Neoplastic, Genomics, Humans, Lung Neoplasms/genetics, Lung Neoplasms/pathology, Molecular Typing, Mutation/genetics, Oncogenes/genetics, Sex Factors, Transcriptome/genetics, Adenocarcinoma of Lung, Cell Cycle Proteins, Biology, Adenocarcinoma, Exon, Germline mutation, microRNA, Adenocarcinoma of the lung, medicine, Gene, Multidisciplinary, Oncogene, Oncogenes, medicine.disease, MET Exon 14 Skipping Mutation, Molecular biology, 3. Good health, Mutation, Transcriptome
Abstract: Adenocarcinoma of the lung is the leading cause of cancer death worldwide. Here we report molecular profiling of 230 resected lung adenocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. High rates of somatic mutation were seen (mean 8.9 mutations per megabase). Eighteen genes were statistically significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations which are mutually exclusive with focal MYC amplification. EGFR mutations were more frequent in female patients, whereas mutations in RBM10 were more common in males. Aberrations in NF1, MET, ERBB2 and RIT1 occurred in 13% of cases and were enriched in samples otherwise lacking an activated oncogene, suggesting a driver role for these events in certain tumours. DNA and mRNA sequence from the same tumour highlighted splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases. MAPK and PI(3)K pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation. These data establish a foundation for classification and further investigations of lung adenocarcinoma molecular pathogenesis.
Published: 2013

194. Inhibitor-Sensitive FGFR2 and FGFR3 Mutations in Lung Squamous Cell Carcinoma

Author: Kwok-Kin Wong, Peter S. Hammerman, Andrey Sivachenko, Joonil Jung, Chandra Sekhar Pedamallu, Matthew D. Wilkerson, Ellen M. Beauchamp, D. Neil Hayes, Nathanael S. Gray, Rachel G. Liao, Qingsong Liu, Matthew Meyerson, Robert I. Haddad, Gad Getz, Trevor J. Pugh, and Jeremy H. Tchaicha
Subjects: musculoskeletal diseases, Cancer Research, Mutation rate, Pathology, medicine.medical_specialty, Indazoles, Lung Neoplasms, Carcinogenesis, medicine.drug_class, Mice, Nude, Ligands, medicine.disease_cause, Article, Receptor tyrosine kinase, Tyrosine-kinase inhibitor, Pazopanib, Mice, Carcinoma, Non-Small-Cell Lung, medicine, Carcinoma, Animals, Humans, Receptor, Fibroblast Growth Factor, Type 3, Receptor, Fibroblast Growth Factor, Type 2, Protein Kinase Inhibitors, Sulfonamides, Mutation, biology, medicine.disease, stomatognathic diseases, Cell Transformation, Neoplastic, Pyrimidines, Oncology, Fibroblast growth factor receptor, Carcinoma, Squamous Cell, NIH 3T3 Cells, Cancer research, biology.protein, Interleukin-3, Dimerization, medicine.drug
Abstract: A comprehensive description of genomic alterations in lung squamous cell carcinoma (lung SCC) has recently been reported, enabling the identification of genomic events that contribute to the oncogenesis of this disease. In lung SCC, one of the most frequently altered receptor tyrosine kinase families is the fibroblast growth factor receptor (FGFR) family, with amplification or mutation observed in all four family members. Here, we describe the oncogenic nature of mutations observed in FGFR2 and FGFR3, each of which are observed in 3% of samples, for a mutation rate of 6% across both genes. Using cell culture and xenograft models, we show that several of these mutations drive cellular transformation. Transformation can be reversed by small-molecule FGFR inhibitors currently being developed for clinical use. We also show that mutations in the extracellular domains of FGFR2 lead to constitutive FGFR dimerization. In addition, we report a patient with an FGFR2-mutated oral SCC who responded to the multitargeted tyrosine kinase inhibitor pazopanib. These findings provide new insights into driving oncogenic events in a subset of lung squamous cancers, and recommend future clinical studies with FGFR inhibitors in patients with lung and head and neck SCC. Cancer Res; 73(16); 5195–205. ©2013 AACR.
Published: 2013
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195. Validation of Interobserver Agreement in Lung Cancer Assessment: Hematoxylin-Eosin Diagnostic Reproducibility for Non–Small Cell Lung Cancer: The 2004 World Health Organization Classification and Therapeutically Relevant Subsets

Author: Kirk D. Jones, William D. Travis, Rebecca Christensen, Christopher R. Cabanski, Thomas E. Stinchcombe, Juneko E. Grilley-Olson, Xiaoying Yin, C. Ryan Miller, Timothy Craig Allen, Thomas V. Colby, Alain C. Borczuk, Mary Beth Beasley, Diane M. Maia, Kevin O. Leslie, Craig F. Hart, Georgean G. Deblois, Dominic T. Moore, Leigh B. Thorne, Göran Elmberger, Michele C. Hayward, Matthew D. Wilkerson, Bahjat F. Qaqish, William K. Funkhouser, Mark A. Socinski, Philip T. Cagle, D. Neil Hayes, Peter M. Banks, Paolo Graziano, and Keith V. Nance
Subjects: Male, Oncology, medicine.medical_specialty, Pathology, Lung Neoplasms, Bevacizumab, Pathology, Surgical, H&E stain, World Health Organization, Article, World health, Pathology and Forensic Medicine, Carcinoma, Non-Small-Cell Lung, Internal medicine, medicine, Carcinoma, Humans, Hematoxylin, Lung cancer, Observer Variation, Internet, Reproducibility, Lung, Staining and Labeling, business.industry, Data Collection, General Medicine, medicine.disease, Medical Laboratory Technology, Pemetrexed, medicine.anatomical_structure, Eosine Yellowish-(YS), Female, business, medicine.drug
Abstract: Precise subtype diagnosis of non-small cell lung carcinoma is increasingly relevant, based on the availability of subtype-specific therapies, such as bevacizumab and pemetrexed, and based on the subtype-specific prevalence of activating epidermal growth factor receptor mutations.To establish a baseline measure of interobserver reproducibility for non-small cell lung carcinoma diagnoses with hematoxylin-eosin for the current 2004 World Health Organization classification, to estimate interobserver reproducibility for the therapeutically relevant squamous/nonsquamous subsets, and to examine characteristics that improve interobserver reproducibility.Primary, resected lung cancer specimens were converted to digital (virtual) slides. Based on a single hematoxylin-eosin virtual slide, pathologists were asked to assign a diagnosis using the 2004 World Health Organization classification. Kappa statistics were calculated for each pathologist-pair for each slide and were summarized by classification scheme, pulmonary pathology expertise, diagnostic confidence, and neoplastic grade.The 12 pulmonary pathology experts and the 12 community pathologists each independently diagnosed 48 to 96 single hematoxylin-eosin digital slides derived from 96 cases of non-small cell lung carcinoma resection. Overall agreement improved with simplification from the comprehensive 44 World Health Organization diagnoses (κ = 0.25) to their 10 major header subtypes (κ = 0.48) and improved again with simplification into the therapeutically relevant squamous/nonsquamous dichotomy (κ = 0.55). Multivariate analysis showed that higher diagnostic agreement was associated with better differentiation, better slide quality, higher diagnostic confidence, similar years of pathology experience, and pulmonary pathology expertise.These data define the baseline diagnostic agreement for hematoxylin-eosin diagnosis of non-small cell lung carcinoma, allowing future studies to test for improved diagnostic agreement with reflex ancillary tests.
Published: 2013
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196. A Genomics-Based Classification of Human Lung Tumors

Author: Sabine Merkelbach-Bruse, Odd Terje Brustugun, Marius Lund-Iversen, Philipp A. Schnabel, Hans Hoffmann, Katharina Koenig, Kato Kambartel, Matthias Scheffler, Reinhard Buettner, Harry J.M. Groen, Jana Fassunke, C. Ligorio, Helen Kuenstlinger, Peter Nuemberg, Sylvie Lantuejoul, William Pao, Philippe Girard, Khosro Hekmat, Johannes Berg, Franziska Gabler, Winfried Randerath, Åslaug Helland, Joerg Saenger, Andreas Schlesinger, Elisabeth Brambilla, Lucia Nogova, Vito Michele Fazio, Monika Serke, Lucia Anna Muscarella, Ines Wilkening, Walburga Engel-Riedel, Sven Perner, Ilona Dahmen, Erich Stoelben, Steinar Solberg, Benjamin Solomon, Hans-Ulrich Schildhaus, Stefan Krueger, Lisa Meffert, Peter M. Schneider, Stefania Damiani, Elke Binot, Katja Schmitz, Toni-Maree Rogers, Ali-Nuri Huenerlituerkoglu, Ulrich Lang, Janine Altmueller, Hannie Sietsma, Chau Nguyen, Lynnette Fernandez-Cuesta, Pierre Validire, Federico Cappuzzo, Christian Mueller, Ulrich Gerigk, Gad Getz, Dirk Behringer, Christian Mattonet, Xin Lu, Wim Timens, Roman K. Thomas, Philippe Lorimier, Masyar Gardizi, Yuan Chen, William D. Travis, Thomas Zander, Prudence A. Russell, Danila Seidel, Marc Bos, Michaela Angelika Kleine, Egbert F. Smit, Matthias Heldwein, Corinna Ludwig, Russell Hyde, Scott L. Carter, Peter J.F. Snijders, Kerstin Albus, Roland Schnell, Alex Soltermann, Michael Hallek, Wolfgang Galetke, Eray Goekkurt, Benjamin Besse, Frauke Leenders, John K. Field, Matthew D. Wilkerson, Roopika Menon, Markus Litt-Lampe, Silvia Querings, Konrad Frank, Yon-Dschun Ko, Holger Moch, Denis Moro-Sibilot, Zoe Wainer, Erik Thunnissen, Lukas C. Heukamp, Walter Weder, Danille A. M. Heideman, Stephan Schmitz, Karin Toepelt, Rainer Kappes, Juergen Wolf, Ingelore Boessmann, Gavin M. Wright, Rainer Fricke, Thomas Muley, Martin L. Sos, Joachim H. Clement, Wolfgang Schulte, Christian Brambilla, Sascha Ansén, Viktor Achter, Jean-Charles Soria, D. Neil Hayes, Martin Peifer, Marcel Reiser, Magdalena Bogus, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Groningen Research Institute for Asthma and COPD (GRIAC), Pathology, Pulmonary medicine, and CCA - Oncogenesis
Subjects: EGFR, Genomics, Biology, Bioinformatics, Genome, GEFITINIB, 03 medical and health sciences, 0302 clinical medicine, Gefitinib, FUSION, medicine, DRIVER MUTATIONS, Lung cancer, 030304 developmental biology, 0303 health sciences, Lung, ACTIVATING MUTATIONS, HUMAN CANCER, Cancer, ADENOCARCINOMA, General Medicine, medicine.disease, OPEN-LABEL, GENE, 3. Good health, SQUAMOUS-CELL CARCINOMAS, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Adenocarcinoma, Human genome, medicine.drug
Abstract: We characterized genome alterations in 1255 clinically annotated lung tumors of all histological subgroups to identify genetically defined and clinically relevant subtypes. More than 55% of all cases had at least one oncogenic genome alteration potentially amenable to specific therapeutic intervention, including several personalized treatment approaches that are already in clinical evaluation. Marked differences in the pattern of genomic alterations existed between and within histological subtypes, thus challenging the original histomorphological diagnosis. Immunohistochemical studies confirmed many of these reassigned subtypes. The reassignment eliminated almost all cases of large cell carcinomas, some of which had therapeutically relevant alterations. Prospective testing of our genomics-based diagnostic algorithm in 5145 lung cancer patients enabled a genome-based diagnosis in 3863 (75%) patients, confirmed the feasibility of rational reassignments of large cell lung cancer, and led to improvement in overall survival in patients with EGFR-mutant or ALK-rearranged cancers. Thus, our findings provide support for broad implementation of genome-based diagnosis of lung cancer.
Published: 2013
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197. Cytokine regulation central to ulipristal-mediated leiomyoma treatment

Author: Joy Britten, William H. Catherino, Lynnette K. Nieman, Minnie Malik, Matthew D. Wilkerson, J. Cox, and X. Zhang
Subjects: 030219 obstetrics & reproductive medicine, business.industry, medicine.medical_treatment, Obstetrics and Gynecology, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Leiomyoma, Cytokine, Reproductive Medicine, 030220 oncology & carcinogenesis, Cancer research, Medicine, Ulipristal, business
Published: 2016
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198. Abstract 4371: Integrated molecular characterization of pheochromocytoma and paraganglioma including a novel, recurrent and prognostic fusion gene

Author: Tobias Else, Vonn Walter, Amy R. Johnson, Matthew D. Wilkerson, Lauren Fishbein, W. Kimryn Rathmell, Stuart R. Jefferys, Brandon Wenz, Shiyun Ling, Bradley A. Murray, Hanse K. Ghayee, Thomas J. Giordano, Sylvia L. Asa, Liza Makowski, Ludmila Danilova, A. Gordon Robertson, K Pacak, Aguirre A. de Cubas, Esther Korpershoek, Arthur S. Tischler, Ignaty Leshchiner, Anne-Paule Gimenez-Roqueplo, Antonio L. Amelio, Katherine L. Nathanson, and Tara M. Lichtenberg
Subjects: 0301 basic medicine, Genetics, Cancer Research, Mutation rate, SDHB, 030209 endocrinology & metabolism, Biology, Germline, Fusion gene, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Germline mutation, Oncology, Fusion transcript, Gene, ATRX
Abstract: Pheochromocytomas (PCC) and paragangliomas (PGL) are tumors of the autonomic nervous system; 25% are metastatic or locally aggressive. Characterization of the inherited basis of disease has identified a variety of underlying germline mutations; however, understanding of somatic alterations remains limited. As part of The Cancer Genome Atlas, we performed the most comprehensive genomic characterization of PCC/PGL to date, by applying eight genomic profiling assays to 173 patients. Despite having a low overall mutation rate per tumor, we observed remarkable diversity in genomic alterations. 27% of patients had a pathogenic germline mutation among eight known familial PCC/PGL susceptibility genes, thus making PCC/PGL the tumor type with the greatest rate of germline mutations in The Cancer Genome Atlas. 38% of patients possessed a somatic driver mutation across 12 genes. RET, NF1 and VHL were affected by both germline and somatic mutation, albeit with different mutation site tendencies. We identified a new somatic driver gene, CSDE1, which had coordinated intron splicing defects, DNA copy number loss, and RNA under-expression, suggesting a loss of function consequence. Most notably, we discovered the first fusion genes in PCC/PGL from RNA and DNA sequencing (7% of patients), demonstrating for the first time that inter-chromosomal translocation and gene fusion is a method of molecular pathogenesis in this disease. Recurrent, novel MAML3 fusion genes spanned three isoforms and were activating based on over-expression of MAML3 and on fusion transcript exonic expression. MAML3 fusion positive tumors had concomitant dual focal DNA amplification of the fusion gene partners and a significantly divergent methylation profile. Another novel driver gene in PCC/PGL, BRAF, was affected by a hotspot somatic mutation and by an activating fusion gene. Through integrated platform analysis, four statistically significant molecular subtypes of PCC/PGL were detected and found to represent divergent molecular etiology – the kinase signaling subtype, the pseudohypoxia subtype, the Wnt-altered subtype, and the cortical admixture subtype. In particular, MAML3 fusions and CSDE1 mutations defined the new Wnt-altered expression subtype of PCC. Adding to the limited set of prognostic markers in PCC/PGL, three molecular markers were positively associated with clinically aggressive disease: germline mutations in SDHB, somatic mutations in ATRX and fusions involving MAML3. Nearly all somatic driver mutations, germline driver mutations and fusion genes were mutually exclusive across the cohort and covered a large portion of the cohort (69%). Our study provides important novel insights into PCC/PGL biology and identifies potential markers for aggressive disease and therapeutic intervention. Citation Format: Lauren Fishbein, Ignaty Leshchiner, Vonn Walter, Ludmila Danilova, A Gordon Robertson, Amy Johnson, Tara Lichtenberg, Bradley A. Murray, Hanse K. Ghayee, Tobias Else, Shiyun Ling, Stuart R. Jefferys, Aguirre A. de Cubas, Brandon Wenz, Esther Korpershoek, Antonio L. Amelio, Liza Makowski, W Kimryn Rathmell, Anne-Paule Gimenez-Roqueplo, Thomas J. Giordano, Sylvia L. Asa, Arthur S. Tischler, The Cancer Genome Atlas Pheochromocytoma and Paraganglioma Analysis Working Group, Karel Pacak, Katherine L. Nathanson, Matthew D. Wilkerson. Integrated molecular characterization of pheochromocytoma and paraganglioma including a novel, recurrent and prognostic fusion gene. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4371.
Published: 2016
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199. EGFR mutation signature in lung adenocarcinoma

Author: David N. Hayes, Jared Weiss, Michele C. Hayward, Wisut Lamlertthon, and Matthew D. Wilkerson
Subjects: Cancer Research, Lung, business.industry, medicine.disease, surgical procedures, operative, medicine.anatomical_structure, Oncology, Egfr mutation, Gene expression, cardiovascular system, Cancer research, medicine, Adenocarcinoma, cardiovascular diseases, business, Signature (topology), circulatory and respiratory physiology
Abstract: e23264Background: The study goals were to characterize and evaluate an EGFR mutation signature developed from the gene expression datasets of lung adenocarcinoma (LAD) patients. Methods: Three LAD ...
Published: 2016
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200. 401 Dermal fibroblasts with loss of TSC2 express increased galectin-3, a potential biomarker for tuberous sclerosis complex

Author: Shaowei Li, Elizabeth A McCart, Rajesh L. Thangapazham, Joel Moss, Jiro Kato, Matthew D. Wilkerson, Clifton L. Dalgard, Peter Klover, J. Wang, and Thomas N. Darling
Subjects: Pathology, medicine.medical_specialty, business.industry, Mesenchyme, Nonsense mutation, Cell Biology, Dermatology, mTORC1, medicine.disease, Biochemistry, Tuberous sclerosis, medicine.anatomical_structure, Amlexanox, Anchoring fibrils, Cancer research, Medicine, TSC1, TSC2, business, Molecular Biology, medicine.drug
Abstract: 400 Amlexanox: Efficacy and mechanism for potential therapy for RDEB V Atanasova, Q Jiang, J Uitto and A South Thomas Jefferson University, Philadelphia, PA Recessive dystrophic epidermolysis bullosa (RDEB) is a severe skin blistering disorder caused by loss-of-function mutations in the COL7A1 gene, which encodes type VII collagen (ColVII). ColVII is the main, if not exclusive, component of anchoring fibrils that adhere the epidermis to the dermal layer of the skin. Mutations in COL7A1 lead to defective anchoring fibrils and subsequent perturbed adhesion between the two skin layers resulting in severe skin fragility and constant wounding without ability to heal. A subgroup of RDEB patients harbors nonsense mutations in COL7A1 which create premature termination codons (PTCs) of translation in the mRNA molecule. This leads to mRNA instability and lack of functional protein synthesized. A group of drugs have been reported for their ability to induce “readthrough” and allow for insertion of an amino acid at the site of PTC, thus producing fulllength protein. The mechanism by which these drugs act is currently not known. Here we focus on a PTC read-through drug, amlexanox, previously approved by the FDA for mouth ulcers. Our data show that amlexanox is able to induce full-length synthesis of ColVII in HpV immortalized RDEB patient derived keratinocytes and fibroblasts, as shown by western blotting. After 48 hours of treatment keratinocytes showed up to 14 fold increase in full-length ColVII protein synthesis as compared to non-treated controls. The same treatment in HpV fibroblasts led up to 3 fold increase in ColVII as compared to non-treated controls, or 25% of normal human fibroblasts. While the mechanism by which amlexanox is able to recover protein synthesis from the PTC containing COL7A1 gene is currently unclear, activation of UPF1 by its phosphorylation has been shown to be required for assembly of mRNA degradation machinery. Our data show that amlexanox treatment increases UPF1 phosphorylation, which may be part of the PTC read-through mechanism. In conclusion, we present data to support amlexanox as a read-through agent for the treatment of RDEB in cases with PTC in COL7A1. 401 Dermal fibroblasts with loss of TSC2 express increased galectin-3, a potential biomarker for tuberous sclerosis complex P Klover, R Thangapazham, J Kato, J Wang, S Li, C Dalgard, M Wilkerson, E Mccart, J Moss and T Darling 1 Dermatology, Uniformed Services University of the Health Sciences, Bethesda, MD, 2 Cardiovascular and Pulmonary Branch, NIH/NHLBI, Bethesda, MD and 3 Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD Tuberous sclerosis complex (TSC) is an autosomal genetic disorder in which tumors form in multiple organs due to biallelic inactivating mutations in TSC1 or TSC2 and increased mTORC1 signaling. In order to discover biomarkers for TSC, we studied our mouse model of TSC with conditional deletion of Tsc2 in dermal mesenchyme (Tsc2cKO), testing the potential clinical relevance of findings using human TSC skin tumors. RNA-sequencing analysis of cultured Tsc2-null and wild-type mouse dermal fibroblasts identified galectin-3 as overexpressed by the mutant cells. Levels of both intracellular and secreted galectin-3 protein were approximately 3-fold greater in Tsc2-null fibroblasts than wild-type fibroblasts. Tsc2-null cells incubated in the presence of 20 nM sirolimus, an mTORC1-inhibitor, showed decreased galectin-3 expression but not to the level of wild-type fibroblasts, suggesting that overexpression of galectin-3 is only partially mTORC1-dependent. Serum levels of galectin-3 were 68% greater (p1⁄40.0015) in Tsc2 cKO than wild-type mice and sirolimus treatment for 4 weeks decreased galectin-3 serum levels 25% (p1⁄40.036) in the Tsc2cKO. Fibroblast-like cells grown from human TSC skin tumors, including angiofibromas, fibrous cephalic plaque, and periungual fibromas, showed greater intracellular and secreted galectin-3 levels than patient normal fibroblasts. Immunohistochemical analysis showed abundant galectin-3 positive dermal cells in TSC skin tumors but nearly absent dermal staining in paired samples of patient normal-appearing skin. Our results demonstrate that loss of TSC2 in dermal fibroblasts is associated with increased galectin-3 and suggest that this molecule should be investigated as a biomarker for TSC and possibly other diseases associated with increased mTORC1 activation.
Published: 2016
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