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; Cancer Genome Atlas Research Network; Rehan Akbani; David A Wheeler; Peter W Laird; Katherine L Nathanson; Victoria K Cortessis; Katherine A Hoadley

doi:10.1016/j.celrep.2018.05.039

Integrated Molecular Characterization of Testicular Germ Cell Tumors

Cell Rep. 2018 Jun 12;23(11):3392-3406. doi: 10.1016/j.celrep.2018.05.039.

Authors

Hui Shen¹, Juliann Shih², Daniel P Hollern³, Linghua Wang⁴, Reanne Bowlby⁵, Satish K Tickoo⁶, Vésteinn Thorsson⁷, Andrew J Mungall⁵, Yulia Newton⁸, Apurva M Hegde⁹, Joshua Armenia¹⁰, Francisco Sánchez-Vega¹⁰, John Pluta¹¹, Louise C Pyle¹², Rohit Mehra¹³, Victor E Reuter⁶, Guilherme Godoy¹⁴, Jeffrey Jones¹⁴, Carl S Shelley¹⁵, Darren R Feldman¹⁶, Daniel O Vidal¹⁷, Davor Lessel¹⁸, Tomislav Kulis¹⁹, Flavio M Cárcano²⁰, Kristen M Leraas²¹, Tara M Lichtenberg²¹, Denise Brooks⁵, Andrew D Cherniack²², Juok Cho²³, David I Heiman²³, Katayoon Kasaian⁵, Minwei Liu²⁴, Michael S Noble²³, Liu Xi²⁵, Hailei Zhang²³, Wanding Zhou¹, Jean C ZenKlusen²⁶, Carolyn M Hutter²⁷, Ina Felau²⁶, Jiashan Zhang²⁶, Nikolaus Schultz¹⁰, Gad Getz²⁸, Matthew Meyerson²², Joshua M Stuart⁸; Cancer Genome Atlas Research Network; Rehan Akbani⁹, David A Wheeler²⁵, Peter W Laird¹, Katherine L Nathanson²⁹, Victoria K Cortessis³⁰, Katherine A Hoadley³¹

Collaborators

Cancer Genome Atlas Research Network:
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 Julia Zhang, Margi Sheth, John A Demchok, Liming Yang, Zhining Wang, Roy Tarnuzzer, Carolyn M Hutter, Heidi J Sofia, Tanja M Davidsen

Affiliations

¹ Van Andel Research Institute, Grand Rapids, MI 49503, USA.
² The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA.
³ Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁴ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Genomic Medicine, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
⁵ Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada.
⁶ Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
⁷ Institute for Systems Biology, Seattle, WA 98109, USA.
⁸ Department of Biomolecular Engineering and Center for Biomolecular Science and Engineering, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
⁹ Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁰ Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
¹¹ Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19105, USA.
¹² Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19105, USA; Division of Genetics and Metabolism, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
¹³ University of Michigan Hospital and Health Systems, 2G332 UH, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA.
¹⁴ Scott Department of Urology, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁵ University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA.
¹⁶ Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
¹⁷ Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, Barretos, Sao Paolo-SP, 14784-400, Brazil.
¹⁸ Institute of Human Genetics, University of Ulm, 89081 Ulm, Germany; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
¹⁹ Department of Urology, University Hospital Center Zagreb, University of Zagreb School of Medicine, 10000 Zagreb, Croatia.
²⁰ Department of Clinical Oncology, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, Barretos, Sao Paolo-SP, 14784-400, Brazil.
²¹ The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
²² The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
²³ The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.
²⁴ Computational Biology Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
²⁵ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
²⁶ National Cancer Institute, NIH, Bethesda, MD 20892, USA.
²⁷ National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
²⁸ The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Massachusetts General Hospital Cancer Center and Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
²⁹ Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19105, USA; Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
³⁰ Departments of Preventive Medicine and Obstetrics and Gynecology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. Electronic address: cortessis_v@med.usc.edu.
³¹ Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: hoadley@med.unc.edu.

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.

Keywords: DNA methylation; KIT; The Cancer Genome Atlas; copy number; exome sequencing; miR-375; nonseminoma; seminoma; testicular germ cell tumors.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

DNA Copy Number Variations
DNA Methylation
Gene Expression Regulation, Neoplastic
Humans
Male
MicroRNAs / metabolism
Neoplasms, Germ Cell and Embryonal / classification
Neoplasms, Germ Cell and Embryonal / metabolism
Neoplasms, Germ Cell and Embryonal / pathology*
Proto-Oncogene Proteins c-kit / genetics
Proto-Oncogene Proteins c-kit / metabolism
Seminoma / metabolism
Seminoma / pathology
Testicular Neoplasms / classification
Testicular Neoplasms / metabolism
Testicular Neoplasms / pathology*
ras Proteins / genetics
ras Proteins / metabolism

Integrated Molecular Characterization of Testicular Germ Cell Tumors

Authors

Collaborators

Affiliations

Abstract

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MeSH terms

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Supplementary concepts

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