Integrated Molecular Characterization of Testicular Germ Cell Tumors

Hui Shen ,Joshua M Stuart ,Minwei Liu ,Linghua Wang ,David I Heiman ,Jiashan Zhang ,Rehan Akbani ,John Pluta ,Katayoon Kasaian ,Gad Getz ,Tara M Lichtenberg ,Katherine L Nathanson ,Darren R Feldman ,Michael S Noble ,Guilherme Godoy ,Ina Felau ,Andrew J Mungall ,Flavio Mavignier Cárcano ,Peter W Laird ,Daniel P Hollern ,Carolyn M Hutter ,Victor E Reuter ,Vésteinn Thórsson ,Carl Simon Shelley ,Kristen Leraas ,David A Wheeler ,Reanne Bowlby ,Louise C Pyle ,Victoria K Cortessis ,Matthew Meyerson ,Daniel Onofre Vidal ,Juok Cho ,Rohit Mehra ,Davor Lessel ,Steven J.m Jones ,Francisco Sánchez-Vega ,Juliann Shih ,Yulia Newton ,Xi Liu ,Wanding Zhou ,Jean C Zenklusen ,Apurva M Hegde ,Tomislav Kuliš ,Hailei Zhang ,Satish K Tickoo ,Andrew D Cherniack ,Nikolaus Schultz ,Joshua Armenia ,Denise Brooks ,Katherine A Hoadley

doi:10.1016/j.celrep.2018.05.039

Abstract

SUMMARYWe 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.

Highlights

The most common malignancy of young adult males of European descent are testicular germ cell tumors (TGCTs) of the type derived from germ cell neoplasia in situ (GCNIS) (Moch et al, 2016)
Histologic Classification Four pathologists reviewed fresh-frozen sections immediately adjacent to the tissue used for molecular analysis to confirm TGCT histology (Figure 1A)
The set of 137 tumors consisted of 72 seminoma, 18 embryonal carcinoma (EC), 9 EC dominant, 3 mature teratoma, 10 mature teratoma dominant, 3 immature teratoma dominant, 5 yolk sac tumor, 8 yolk sac tumor dominant, and 9 mixed tumors with no dominant component (Table S1)

Summary

Introduction

The most common malignancy of young adult males of European descent are testicular germ cell tumors (TGCTs) of the type derived from germ cell neoplasia in situ (GCNIS) (Moch et al, 2016). There are two major histologic types: pure classic seminoma and nonseminomatous germ cell tumors (NSGCTs). The latter, comprising embryonal carcinoma (EC), choriocarcinoma, 3392 Cell Reports 23, 3392–3406, June 12, 2018 a 2018 The Author(s). The Cancer Genome Atlas Research Network, Rehan Akbani, David A.

Results

Discussion

Conclusion