Integrated Molecular Characterization of Testicular Germ Cell Tumors

Hui Shen; Juliann Shih; Daniel P. Hollern; Linghua Wang; Reanne Bowlby; Satish K. Tickoo; Vésteinn Thorsson; Andrew J. Mungall; Yulia Newton; Apurva M. Hegde; Joshua Armenia; Francisco Sánchez-Vega; John Pluta; Louise C. Pyle; Rohit Mehra; Victor E. Reuter; Guilherme Godoy; Jeffrey Jones; Carl S. Shelley; Darren R. Feldman; Daniel O. Vidal; Davor Lessel; Tomislav Kulis; Flavio M. Cárcano; Kristen M. Leraas; Tara M. Lichtenberg; Denise Brooks; Andrew D. Cherniack; Juok Cho; David I. Heiman; Katayoon Kasaian; Minwei Liu; Michael S. Noble; Liu Xi; Hailei Zhang; Wanding Zhou; Jean C. ZenKlusen; Carolyn M. Hutter; Ina Felau; Jiashan Zhang; Nikolaus Schultz; Gad Getz; Matthew Meyerson; Joshua M. Stuart; Rehan Akbani; David A. Wheeler; Peter W. Laird; Katherine L. Nathanson; Victoria K. Cortessis; Katherine A. Hoadley; Linghua Wang; Liu Xi; David Wheeler; Daniel Hughes; Kyle Covington; Joy C. Jayaseelan; Viktoriya Korchina; Lora Lewis; Jianhong Hu; HarshaVardhan Doddapaneni; Donna Muzny; Richard Gibbs; Katherine A. Hoadley; Daniel Hollern; Benjamin G. Vincent; Shengjie Chai; Christof C. Smith; J. Todd Auman; Yan Shi; Shaowu Meng; Tara Skelly; Donghui Tan; Umadevi Veluvolu; Piotr A. Mieczkowski; Corbin D. Jones; Matthew D. Wilkerson; Saianand Balu; Tom Bodenheimer; Alan P. Hoyle; Stuart R. Jefferys; Lisle E. Mose; Janae V. Simons; Matthew G. Soloway; Jeffrey Roach; Joel S. Parker; D. Neil Hayes; Charles M. Perou; Juliann Shih; Andrew D. Cherniack; Matthew Meyerson; Gordon Saksena; Carrie Cibulskis; Steven E. Schumacher; Rameen Beroukhim; Stacey B. Gabriel; Reanne Bowlby; Andrew J. Mungall; Denise Brooks; Katayoon Kasaian; Adrian Ally; Miruna Balasundaram; Rebecca Carlsen; Dorothy Cheung; Eric Chuah; Noreen Dhalla; Robert A. Holt; Steven J.M. Jones; Yussanne Ma; Michael Mayo; Richard A. Moore; A. Gordon Robertson; Jacqueline E. Schein; Payal Sipahimalani; Angela Tam; Nina Thiessen; Tina Wong; Marco A. Marra; Hui Shen; Wanding Zhou; Peter W. Laird; Daniel J. Weisenberger; David J. Van Den Berg; Phillip H. Lai; Mario Berrios; Andrea Holbrook; Moiz S. Bootwalla; Dennis T. Maglinte; Joshua Armenia; Francisco Sánchez-Vega; Nikolaus Schultz; Debyani Chakravarty; Jianjiong Gao; Zachary Heins; Ritika Kundra; Angelica Ochoa; Minwei Liu; Chris Sander; Marc Ladanyi; Vesteinn Thorsson; Amie J. Radenbaugh; Yulia Newton; Joshua M. Stuart; Juok Cho; David I. Heiman; Michael S. Noble; Hailei Zhang; Gad Getz; Nils Gehlenborg; Gordon Saksena; Doug Voet; Pei Lin; Scott Frazer; Jaegil Kim; Michael S. Lawrence; Sam Meier; Timothy Defreitas; Lynda Chin; Apurva M. Hegde; Rehan Akbani; John N. Weinstein; Wenbin Liu; Gordon B. Mills; Yiling Lu; Louise C. Pyle; John Pluta; Katherine L. Nathanson; Satish K. Tickoo; Victor E. Reuter; Rohit Mehra; Leendert Looijenga; Alan H. Bryce; Flavio M. Cárcano; André L. Carvalho; Victoria K. Cortessis; Darren Feldman; Guilherme Godoy; Michael Ittmann; Jeffrey Jones; Tomislav Kulis; Seth Lerner; Davor Lessel; Katherine L. Nathanson; Carl S. Shelley; Daniel O. Vidal; Kristen M. Leraas; Tara M. Lichtenberg; Jay Bowen; Julie M. Gastier-Foster; Mark Gerken; Carmen Helsel; Nilsa C. Ramirez; Lisa Wise; Erik Zmuda; Sandra Cottingham; David Chesla; Charles Saller; Katherine Tarvin; Luiz Fernando Lopes; Cristovam Scapulatempo-Neto; Natália D.A. Aredes; Wolter Oosterhuis; Ad Gillis; Hans Stoop; Wil Eijkenboom; George Sandusky; Sue Ellen Martin; Manju Aron; Siamak Daneshmand; Hooman Djaladat; David Quinn; Tanya Dorff; Jochen K. Lennerz; Leigh B. Thorne; Marija Gamulin; Zeljko Kastelan; 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; Ye Wu; Martin L. Ferguson; Jean C. Zenklusen; Ina Felau; Jiashan  Zhang; Margi Sheth; John A. Demchok; Liming Yang; Zhining Wang; Roy Tarnuzzer; Carolyn M. Hutter; Heidi J. Sofia; Tanja M. Davidsen

Integrated Molecular Characterization of Testicular Germ Cell Tumors

2018

Summary: 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. : Shen et al. identify molecular characteristics that classify testicular germ cell tumor types, including a separate subset of seminomas defined by KIT mutations. This provides a set of candidate biomarkers for risk stratification and potential therapeutic targeting. Keywords: The Cancer Genome Atlas, testicular germ cell tumors, seminoma, nonseminoma, DNA methylation, exome sequencing, KIT, copy number, miR-375

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