Germ-cell tumours (GCTs) are derived from germ cells and occur most frequently in the testes. GCTs are histologically heterogeneous and distinctly curable with chemotherapy. Gains of chromosome arm 12p and aneuploidy are nearly universal in GCTs, but specific somatic genomic features driving tumour initiation, chemosensitivity and progression are incompletely characterized. Here, using clinical whole-exome and transcriptome sequencing of precursor, primary (testicular and mediastinal) and chemoresistant metastatic human GCTs, we show that the primary somatic feature of GCTs is highly recurrent chromosome arm level amplifications and reciprocal deletions (reciprocal loss of heterozygosity), variations that are significantly enriched in GCTs compared to 19 other cancer types. These tumours also acquire KRAS mutations during the development from precursor to primary disease, and primary testicular GCTs (TGCTs) are uniformly wild type for TP53. In addition, by functional measurement of apoptotic signalling (BH3 profiling) of fresh tumour and adjacent tissue, we find that primary TGCTs have high mitochondrial priming that facilitates chemotherapy-induced apoptosis. Finally, by phylogenetic analysis of serial TGCTs that emerge with chemotherapy resistance, we show how TGCTs gain additional reciprocal loss of heterozygosity and that this is associated with loss of pluripotency markers (NANOG and POU5F1) in chemoresistant teratomas or transformed carcinomas. Our results demonstrate the distinct genomic features underlying the origins of this disease and associated with the chemosensitivity phenotype, as well as the rare progression to chemoresistance. These results identify the convergence of cancer genomics, mitochondrial priming and GCT evolution, and may provide insights into chemosensitivity and resistance in other cancers.
Nature. 2016 Nov 30 [Epub]
Amaro Taylor-Weiner, Travis Zack, Elizabeth O'Donnell, Jennifer L Guerriero, Brandon Bernard, Anita Reddy, G Celine Han, Saud AlDubayan, Ali Amin-Mansour, Steven E Schumacher, Kevin Litchfield, Clare Turnbull, Stacey Gabriel, Rameen Beroukhim, Gad Getz, Scott L Carter, Michelle S Hirsch, Anthony Letai, Christopher Sweeney, Eliezer M Van Allen
Division of Medical Sciences, Harvard University, Boston, Massachusetts 02115, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA., Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA., Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA., Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Massachusetts 02115, USA., Division of Genetics and Epidemiology, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK., Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.