Integrated Molecular Characterization of Testicular Germ Cell Tumors.

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.

• Authors: 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
• Journal: Cell reports (Cell Rep) Vol. 23 Issue 11 Pg. 3392-3406 (06 12 2018) ISSN: 2211-1247 [Electronic] United States
• PMID: 29898407 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• MicroRNAs
• Proto-Oncogene Proteins c-kit
• ras Proteins

Topics

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