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

Integrated Molecular Characterization of Testicular Germ Cell Tumors.

Collaborators (191)

Wang L, Xi L, Wheeler D, Hughes D, Covington K, Jayaseelan JC, Korchina V, Lewis L, Hu J, Doddapaneni H, Muzny D, Gibbs R, Hoadley KA, Hollern D, Vincent BG, Chai S, Smith CC, Auman JT, Shi Y, Meng S, Skelly T, Tan D, Veluvolu U, Mieczkowski PA, Jones CD, Wilkerson MD, Balu S, Bodenheimer T, Hoyle AP, Jefferys SR, Mose LE, Simons JV, Soloway MG, Roach J, Parker JS, Hayes DN, Perou CM, Shih J, Cherniack AD, Meyerson M, Saksena G, Cibulskis C, Schumacher SE, Beroukhim R, Gabriel SB, Bowlby R, Mungall AJ, Brooks D, Kasaian K, Ally A, Balasundaram M, Carlsen R, Cheung D, Chuah E, Dhalla N, Holt RA, Jones SJM, Ma Y, Mayo M, Moore RA, Robertson AG, Schein JE, Sipahimalani P, Tam A, Thiessen N, Wong T, Marra MA, Shen H, Zhou W, Laird PW, Weisenberger DJ, Van Den Berg DJ, Lai PH, Berrios M, Holbrook A, Bootwalla MS, Maglinte DT, Armenia J, Sánchez-Vega F, Schultz N, Chakravarty D, Gao J, Heins Z, Kundra R, Ochoa A, Liu M, Sander C, Ladanyi M, Thorsson V, Radenbaugh AJ, Newton Y, Stuart JM, Cho J, Heiman DI, Noble MS, Zhang H, Getz G, Gehlenborg N, Saksena G, Voet D, Lin P, Frazer S, Kim J, Lawrence MS, Meier S, Defreitas T, Chin L, Hegde AM, Akbani R, Weinstein JN, Liu W, Mills GB, Lu Y, Pyle LC, Pluta J, Nathanson KL, Tickoo SK, Reuter VE, Mehra R, Looijenga L, Bryce AH, Cárcano FM, Carvalho AL, Cortessis VK, Feldman D, Godoy G, Ittmann M, Jones J, Kulis T, Lerner S, Lessel D, Nathanson KL, Shelley CS, Vidal DO, Leraas KM, Lichtenberg TM, Bowen J, Gastier-Foster JM, Gerken M, Helsel C, Ramirez NC, Wise L, Zmuda E, Cottingham S, Chesla D, Saller C, Tarvin K, Lopes LF, Scapulatempo-Neto C, Aredes NDA, Oosterhuis W, Gillis A, Stoop H, Eijkenboom W, Sandusky G, Martin SE, Aron M, Daneshmand S, Djaladat H, Quinn D, Dorff T, Lennerz JK, Thorne LB, Gamulin M, Kastelan Z, Hudolin T, Kubisch C, Boice L, Huang M, Perou AH, Rathmell WK, Pihl T, Wan Y, Sun Q, Naresh R, Chudamani S, Liu J, Lolla L, Wu Y, Ferguson ML, Zenklusen JC, Felau I, Zhang JJ, Sheth M, Demchok JA, Yang L, Wang Z, Tarnuzzer R, Hutter CM, Sofia HJ, Davidsen TM.

Author information

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

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