Genomic evolution and chemoresistance in germ-cell tumours.
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Date
2016-11-30Author
Taylor-Weiner, A
Zack, T
O'Donnell, E
Guerriero, JL
Bernard, B
Reddy, A
Han, GC
AlDubayan, S
Amin-Mansour, A
Schumacher, SE
Litchfield, K
Turnbull, C
Gabriel, S
Beroukhim, R
Getz, G
Carter, SL
Hirsch, MS
Letai, A
Sweeney, C
Van Allen, EM
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
Mitochondria
Humans
Neoplasms, Germ Cell and Embryonal
Teratoma
Testicular Neoplasms
Neoplasm Metastasis
Disease Progression
Genomics
Evolution, Molecular
Phylogeny
Apoptosis
Drug Resistance, Neoplasm
Mutation
Loss of Heterozygosity
Genome, Human
Male
Tumor Suppressor Protein p53
Proto-Oncogene Proteins p21(ras)
Octamer Transcription Factor-3
Transcriptome
Exome
Nanog Homeobox Protein
Research team
Molecular & Population Genetics
Language
eng
Date accepted
2016-11-02
License start date
2016-11
Citation
Nature, 2016, 540 (7631), pp. 114 - 118
Publisher
NATURE PUBLISHING GROUP