title: Genomic evolution and chemoresistance in germ-cell tumours.
abstract: 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.
authors.affiliation: Division of Medical Sciences, Harvard University, Boston, Massachusetts 02115, USA.|Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
authors.forename: Amaro
authors.initials: A
authors.lastname: Taylor-Weiner
authors.affiliation: Division of Medical Sciences, Harvard University, Boston, Massachusetts 02115, USA.|Health Sciences and Technology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Travis
authors.initials: T
authors.lastname: Zack
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Department of Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: O'Donnell
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Guerriero
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Brandon
authors.initials: B
authors.lastname: Bernard
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Anita
authors.initials: A
authors.lastname: Reddy
authors.affiliation: Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: G Celine
authors.initials: GC
authors.lastname: Han
authors.affiliation: Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Massachusetts 02115, USA.|Department of Medicine, King Saud bin Abdulaziz University for Health Sciences, Saudi Arabia.
authors.forename: Saud
authors.initials: S
authors.lastname: AlDubayan
authors.affiliation: Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Amin-Mansour
authors.affiliation: Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Schumacher
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK.|William Harvey Research Institute, Queen Mary University London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: Litchfield
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK.|William Harvey Research Institute, Queen Mary University London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Clare
authors.initials: C
authors.lastname: Turnbull
authors.affiliation: Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
authors.forename: Stacey
authors.initials: S
authors.lastname: Gabriel
authors.affiliation: Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Rameen
authors.initials: R
authors.lastname: Beroukhim
authors.affiliation: Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.|Cancer Center and Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.affiliation: Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.|Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215 , USA.|Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Carter
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Hirsch
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Letai
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Sweeney
authors.affiliation: Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Eliezer M
authors.initials: EM
authors.lastname: Van Allen
mesh_terms: D017209:Apoptosis; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D019143:Evolution, Molecular; D059472:Exome / Q000235:genetics; D015894:Genome, Human / Q000235:genetics*; D023281:Genomics; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D000071317:Nanog Homeobox Protein / Q000172:deficiency; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D050814:Octamer Transcription Factor-3 / Q000172:deficiency; D010802:Phylogeny; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D013724:Teratoma / Q000235:genetics; D013736:Testicular Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D059467:Transcriptome / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: C117307:KRAS protein, human; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D016283:Proto-Oncogene Proteins p21(ras)