Integrated Molecular Characterization of Testicular Germ Cell Tumors.
Shen H1, Shih J2, Hollern DP3, Wang L4, Bowlby R5, Tickoo SK6, Thorsson V7, Mungall AJ5, Newton Y8, Hegde AM9, Armenia J10, Sánchez-Vega F10, Pluta J11, Pyle LC12, Mehra R13, Reuter VE6, Godoy G14, Jones J14, Shelley CS15, Feldman DR16, Vidal DO17, Lessel D18, Kulis T19, Cárcano FM20, Leraas KM21, Lichtenberg TM21, Brooks D5, Cherniack AD22, Cho J23, Heiman DI23, Kasaian K5, Liu M24, Noble MS23, Xi L25, Zhang H23, Zhou W1, ZenKlusen JC26, Hutter CM27, Felau I26, Zhang J26, Schultz N10, Getz G28, Meyerson M22, Stuart JM8; Cancer Genome Atlas Research Network, Akbani R9, Wheeler DA25, Laird PW1, Nathanson KL29, Cortessis VK30, Hoadley KA31.
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.
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