Integrated Molecular Characterization of Testicular Germ Cell Tumors
Hui Shen(Van Andel Institute), Juliann Shih(Broad Institute), Daniel P. Hollern(University of North Carolina at Chapel Hill), Linghua Wang(The University of Texas MD Anderson Cancer Center), Reanne Bowlby(BC Cancer Agency), Satish K. Tickoo(Memorial Sloan Kettering Cancer Center), Vésteinn Thórsson(Institute for Systems Biology), Andrew J. Mungall(BC Cancer Agency), Yulia Newton(University of California, Santa Cruz), Apurva M. Hegde(The University of Texas MD Anderson Cancer Center), Joshua Armenia(Memorial Sloan Kettering Cancer Center), Francisco Sánchez-Vega(Memorial Sloan Kettering Cancer Center), John Pluta(University of Pennsylvania), Louise C. Pyle(Children's Hospital of Philadelphia), Rohit Mehra(University of Michigan), Victor E. Reuter(Memorial Sloan Kettering Cancer Center), Guilherme Godoy(Baylor College of Medicine), Jeffrey Jones(Baylor College of Medicine), Carl Simon Shelley(University of Wisconsin–Madison), Darren R. Feldman(Memorial Sloan Kettering Cancer Center), Daniel Onofre Vidal(Hospital de Câncer de Barretos), Davor Lessel(Universität Hamburg), Tomislav Kuliš(University Hospital Centre Zagreb), Flavio Mavignier Cárcano(Hospital de Câncer de Barretos), Kristen Leraas(Nationwide Children's Hospital), Tara M. Lichtenberg(Nationwide Children's Hospital), Denise Brooks(BC Cancer Agency), Andrew D. Cherniack(Broad Institute), Juok Cho(Broad Institute), David I. Heiman(Broad Institute), Katayoon Kasaian(BC Cancer Agency), Minwei Liu(Memorial Sloan Kettering Cancer Center), Michael S. Noble(Broad Institute), Xi Liu(Baylor College of Medicine), Hailei Zhang(Broad Institute), Wanding Zhou(Van Andel Institute), Jean C. Zenklusen(National Cancer Institute), Carolyn M. Hutter(National Human Genome Research Institute), Ina Felau(National Cancer Institute), Jiashan Zhang(Memorial Sloan Kettering Cancer Center), Nikolaus Schultz(Broad Institute), Gad Getz(Broad Institute), Matthew Meyerson(University of California, Santa Cruz), Joshua M. Stuart(The University of Texas MD Anderson Cancer Center), Linghua Wang(The University of Texas MD Anderson Cancer Center), Xi Liu(Van Andel Institute), David A. Wheeler(Baylor College of Medicine), Daniel Hughes(University of Southern California), Kyle R. Covington(University of North Carolina at Chapel Hill), Joy C. Jayaseelan(The University of Texas MD Anderson Cancer Center), Viktoriya Korchina(Baylor College of Medicine), Lora Lewis(Baylor College of Medicine), Hai Hu(Hospital de Câncer de Barretos), HarshaVardhan Doddapaneni, Donna M. Muzny, Richard A. Gibbs, Katherine A. Hoadley(University of North Carolina at Chapel Hill), Daniel P. Hollern(University of North Carolina at Chapel Hill), Benjamin G. Vincent, Shengjie Chai, Christof C. Smith, J. Todd Auman(University of North Carolina at Chapel Hill), Yan Shi(University of North Carolina at Chapel Hill), Shaowu Meng, Tara Skelly, Donghui Tan, Umadevi Veluvolu, Piotr A. Mieczkowski(Broad Institute), Corbin D. Jones, Matthew D. Wilkerson(Nationwide Children's Hospital), Saianand Balu, Tom Bodenheimer, Alan P. Hoyle, Stuart R. Jefferys(Baylor College of Medicine), Lisle E. Mose, Janae V. Simons, Matthew G. Soloway(University Hospital Centre Zagreb), Jeffrey Roach, Joel S. Parker, D. Neil Hayes, Charles M. Perou, Juliann Shih(Dana-Farber Cancer Institute), Andrew D. Cherniack(Baylor College of Medicine), Matthew Meyerson(Dana-Farber Cancer Institute), Gordon Saksena, Carrie Cibulskis, Steven E. Schumacher(Broad Institute), Rameen Beroukhim(Broad Institute), Stacey Gabriel(Broad Institute), Reanne Bowlby(BC Cancer Agency), Andrew J. Mungall(BC Cancer Agency), Denise Brooks(BC Cancer Agency), Katayoon Kasaian(BC Cancer Agency), Adrian Ally, Miruna Balasundaram(BC Cancer Agency), Rebecca Carlsen(BC Cancer Agency), Dorothy Cheung(BC Cancer Agency), Eric Chuah(BC Cancer Agency), Noreen Dhalla, Robert A. Holt, Steven J.M. Jones, Yussanne Ma, Michael Mayo, Richard A. Moore, A. Gordon Robertson, Jacqueline E. Schein(Baylor College of Medicine), Payal Sipahimalani(Broad Institute), Angela Tam(Broad Institute), Nina Thiessen, Tina Wong, Marco A. Marra, Hui Shen(Van Andel Institute), Wanding Zhou(Van Andel Institute), Peter W. Laird(Van Andel Institute), Daniel J. Weisenberger, David Van Den Berg, Phillip H. Lai(Van Andel Institute), Mario Berríos(Van Andel Institute), Andrea Holbrook(Van Andel Institute), Moiz S. Bootwalla, Dennis T. Maglinte, Joshua Armenia(Van Andel Institute), Francisco Sánchez-Vega(Memorial Sloan Kettering Cancer Center), Nikolaus Schultz(Memorial Sloan Kettering Cancer Center), Debyani Chakravarty, Jianjiong Gao, Zachary Heins(Memorial Sloan Kettering Cancer Center), Ritika Kundra(Memorial Sloan Kettering Cancer Center), Angelica Ochoa(Memorial Sloan Kettering Cancer Center), Minwei Liu(Memorial Sloan Kettering Cancer Center), Chris Sander, Marc Ladanyi, Vésteinn Thórsson(Institute for Systems Biology), Amie Radenbaugh, Yulia Newton(Memorial Sloan Kettering Cancer Center), Joshua M. Stuart(University of California, Santa Cruz), Juok Cho(Broad Institute), David I. Heiman(Broad Institute), Michael S. Noble(Broad Institute), Hailei Zhang(Broad Institute), Gad Getz(Broad Institute), Nils Gehlenborg(Broad Institute), Gordon Saksena(Broad Institute), Doug Voet(Broad Institute), Pei Lin(Broad Institute), Scott Frazer(Broad Institute), Jaegil Kim, Michael S. Lawrence, Sam Meier, Timothy Defreitas(The University of Texas MD Anderson Cancer Center), Lynda Chin, Apurva M. Hegde(The University of Texas MD Anderson Cancer Center), Rehan Akbani(Broad Institute), John N. Weinstein, Wenbin Liu, Gordon B. Mills, Yiling Lu(The University of Texas MD Anderson Cancer Center), Louise C. Pyle(Children's Hospital of Philadelphia), John Pluta(University of Pennsylvania), Katherine L. Nathanson(Baylor College of Medicine), Satish K. Tickoo(Memorial Sloan Kettering Cancer Center), Victor E. Reuter(Memorial Sloan Kettering Cancer Center), Rohit Mehra(Children's Hospital of Philadelphia), Leendert H. J. Looijenga(University of Pennsylvania), Alan H. Bryce(University of Pennsylvania), Flavio Mavignier Cárcano(Memorial Sloan Kettering Cancer Center), André Lopes Carvalho(Memorial Sloan Kettering Cancer Center), Victoria K. Cortessis(University of Southern California), Darren R. Feldman(Memorial Sloan Kettering Cancer Center), Guilherme Godoy(Baylor College of Medicine), Michael Ittmann(Hospital de Câncer de Barretos), Jeffrey Jones(Baylor College of Medicine), Tomislav Kuliš(University of Southern California), Seth P. Lerner(Memorial Sloan Kettering Cancer Center), Davor Lessel(Universität Hamburg), Katherine L. Nathanson(Broad Institute), Carl Simon Shelley(University of Wisconsin–Madison), Daniel Onofre Vidal(University Hospital Centre Zagreb), Kristen Leraas(Nationwide Children's Hospital), Tara M. Lichtenberg(Nationwide Children's Hospital), Jay Bowen(University of Pennsylvania), Julie M. Gastier‐Foster(University of Wisconsin–Madison), Mark Gerken(Hospital de Câncer de Barretos), Carmen Helsel(Nationwide Children's Hospital), Nilsa C. Ramirez(Nationwide Children's Hospital), Lisa Wise, Erik Zmuda, Sandra Cottingham, David Chesla, Charles Saller, Katherine Tarvin, Luiz Fernando Lopes, Cristovam Scapulatempo‐Neto, Natália D. Aredes(Baylor College of Medicine), Wolter Oosterhuis, Ad Gillis(University of North Carolina at Chapel Hill), Hans Stoop, W M H Eijkenboom, George Sandusky, Sue Martin, Manju Aron(University of North Carolina at Chapel Hill), Siamak Daneshmand(University of Pennsylvania), Hooman Djaladat, David I. Quinn, Tanya B. Dorff, Jochen K. Lennerz, Leigh B. Thorne, Marija Gamulin, Željko Kaštelan(Baylor College of Medicine), Tvrtko Hudolin, Christian Kubisch, Lori Boice, Mei Huang, Amy H. Perou, W. Kimryn Rathmell, Todd Pihl, Yunhu Wan, Qiang Sun, Rashi Naresh, Sudha Chudamani, Jia Liu, Laxmi Lolla(Van Andel Institute), Ye Wu, Martin L. Ferguson, Jean C. Zenklusen(National Cancer Institute), Ina Felau(Baylor College of Medicine), Jiashan Zhang(National Cancer Institute), Margi Sheth(Broad Institute), John A. Demchok, Liming Yang(National Cancer Institute), Zhining Wang(National Cancer Institute), Roy Tarnuzzer(National Cancer Institute), Carolyn M. Hutter(National Human Genome Research Institute), Heidi J. Sofia(University of Pennsylvania), Tanja M. Davidsen, Rehan Akbani(The University of Texas MD Anderson Cancer Center), David A. Wheeler(Baylor College of Medicine), Peter W. Laird(Van Andel Institute), Katherine L. Nathanson(University of Pennsylvania), Victoria K. Cortessis(University of Southern California), Katherine A. Hoadley(University of North Carolina at Chapel Hill)
Cited by 458Open Access
Abstract
We studied 137 primary testicular germ cell tumors (TGCTs) using high-dimensional assays of genomic, epigenomic, transcriptomic, and proteomic features. These tumors exhibited high aneuploidy and a paucity of somatic mutations. Somatic mutation of only three genes achieved significance-KIT, KRAS, and NRAS-exclusively in samples with seminoma components. Integrated analyses identified distinct molecular patterns that characterized the major recognized histologic subtypes of TGCT: seminoma, embryonal carcinoma, yolk sac tumor, and teratoma. Striking differences in global DNA methylation and microRNA expression between histology subtypes highlight a likely role of epigenomic processes in determining histologic fates in TGCTs. We also identified a subset of pure seminomas defined by KIT mutations, increased immune infiltration, globally demethylated DNA, and decreased KRAS copy number. We report potential biomarkers for risk stratification, such as miRNA specifically expressed in teratoma, and others with molecular diagnostic potential, such as CpH (CpA/CpC/CpT) methylation identifying embryonal carcinomas.
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