Genomic consequences of aberrant DNA repair mechanisms stratify ovarian cancer histotypes

Sohrab Shah, David Huntsman and colleagues report the genomic analysis of 133 ovarian cancers spanning different subtypes. They identify seven subgroups using point mutation and structural variation signatures and use these genomic features to stratify ovarian cancers both between and within histoty...

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Bibliographic Details
Published in:Nature genetics Vol. 49; no. 6; pp. 856 - 865
Main Authors: Wang, Yi Kan, Bashashati, Ali, Anglesio, Michael S, Cochrane, Dawn R, Grewal, Diljot S, Ha, Gavin, McPherson, Andrew, Horlings, Hugo M, Senz, Janine, Prentice, Leah M, Karnezis, Anthony N, Lai, Daniel, Aniba, Mohamed R, Zhang, Allen W, Shumansky, Karey, Siu, Celia, Wan, Adrian, McConechy, Melissa K, Li-Chang, Hector, Tone, Alicia, Provencher, Diane, de Ladurantaye, Manon, Fleury, Hubert, Okamoto, Aikou, Yanagida, Satoshi, Yanaihara, Nozomu, Saito, Misato, Mungall, Andrew J, Moore, Richard, Marra, Marco A, Gilks, C Blake, Mes-Masson, Anne-Marie, McAlpine, Jessica N, Aparicio, Samuel, Huntsman, David G, Shah, Sohrab P
Format: Journal Article
Language:English
Published: New York Nature Publishing Group US 01.06.2017
Nature Publishing Group
Subjects:
45/77
49/39
631/114/2785
631/67/1517/1709
Aberration
Age
Agriculture
Animal Genetics and Genomics
Biomarkers
Biomedicine
BRCA1 protein
BRCA1 Protein - genetics
BRCA2 protein
BRCA2 Protein - genetics
Breast cancer
Cancer
Cancer Research
Care and treatment
Clustering
Colleges & universities
Deamination
Deoxyribonucleic acid
Development and progression
DNA
DNA methylation
DNA repair
DNA Repair - genetics
Endometriosis - complications
Endometriosis - genetics
Female
Gene expression
Gene Expression Regulation, Neoplastic
Gene Function
Genetic aspects
Genetic testing
Genome, Human
Genomes
Gynecology
Health aspects
Human Genetics
Humans
Inversions
Medical screening
Medicine
Microsatellite instability
Mutation
Obstetrics
Oncology
Ovarian cancer
Ovarian Neoplasms - drug therapy
Ovarian Neoplasms - genetics
Ovarian Neoplasms - mortality
Ovarian Neoplasms - pathology
Point mutation
Prognosis
Repair
Signatures
Stability
Strata
Stratigraphy
Subgroups
Survival
Trends
Tumors
Canada
ISSN:1061-4036, 1546-1718, 1546-1718
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Summary:Sohrab Shah, David Huntsman and colleagues report the genomic analysis of 133 ovarian cancers spanning different subtypes. They identify seven subgroups using point mutation and structural variation signatures and use these genomic features to stratify ovarian cancers both between and within histotypes. We studied the whole-genome point mutation and structural variation patterns of 133 tumors (59 high-grade serous (HGSC), 35 clear cell (CCOC), 29 endometrioid (ENOC), and 10 adult granulosa cell (GCT)) as a substrate for class discovery in ovarian cancer. Ab initio clustering of integrated point mutation and structural variation signatures identified seven subgroups both between and within histotypes. Prevalence of foldback inversions identified a prognostically significant HGSC group associated with inferior survival. This finding was recapitulated in two independent cohorts ( n = 576 cases), transcending BRCA1 and BRCA2 mutation and gene expression features of HGSC. CCOC cancers grouped according to APOBEC deamination (26%) and age-related mutational signatures (40%). ENOCs were divided by cases with microsatellite instability (28%), with a distinct mismatch-repair mutation signature. Taken together, our work establishes the potency of the somatic genome, reflective of diverse DNA repair deficiencies, to stratify ovarian cancers into distinct biological strata within the major histotypes.
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ISSN:1061-4036
1546-1718
1546-1718
DOI:10.1038/ng.3849