Title

Integrated Molecular Characterization of Testicular Germ Cell Tumors

Authors

Hui Shen, Van Andel Research Institute
Juliann Shih, Massachusetts Institute of Technology
Daniel P. Hollern, The University of North Carolina at Chapel Hill
Daniel P. Hollern, The University of North Carolina at Chapel Hill
Linghua Wang, Baylor College of Medicine
Reanne Bowlby, British Columbia Cancer Agency
Satish K. Tickoo, Memorial Sloan-Kettering Cancer Center
Vésteinn Thorsson, Institute for Systems Biology
Andrew J. Mungall, British Columbia Cancer Agency
Yulia Newton, University of California, Santa Cruz
Apurva M. Hegde, 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 Perelman School of Medicine
Louise C. Pyle, University of Pennsylvania Perelman School of Medicine
Rohit Mehra, University of Michigan Hospital
Victor E. Reuter, Memorial Sloan-Kettering Cancer Center
Guilherme Godoy, Baylor College of Medicine
Jeffrey Jones, Baylor College of Medicine
Carl S. Shelley, University of Wisconsin School of Medicine and Public Health
Darren R. Feldman, Memorial Sloan-Kettering Cancer Center
Daniel O. Vidal, Hospital de Câncer de Barretos
Davor Lessel, Universität Ulm
Tomislav Kulis, KBC Zagreb
Flavio M. Cárcano, Hospital de Câncer de Barretos
Kristen M. Leraas, Research Institute at Nationwide Childrens Hospital
Tara M. Lichtenberg, Research Institute at Nationwide Childrens Hospital
Denise Brooks, British Columbia Cancer Agency
Andrew D. Cherniack, Massachusetts Institute of Technology
Juok Cho, Massachusetts Institute of Technology
David I. Heiman, Massachusetts Institute of Technology
Katayoon Kasaian, British Columbia Cancer Agency

Document Type

Journal Article

Publication Date

6-12-2018

Journal

Cell Reports

Volume

23

DOI

10.1016/j.celrep.2018.05.039

Keywords

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

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. 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.

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