期刊
NATURE GENETICS
卷 49, 期 6, 页码 856-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3849
关键词
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资金
- BC Cancer Foundation
- OvCaRe
- Gray Family Ovarian Clear Cell Carcinoma Research Resource
- Terry Fox Research Institute New Investigator grant
- Canadian Cancer Society Research Institute Impact grant
- Reseau de Recherche sur le Cancer
- Fonds de Recherche Quebec Sante
- Canadian Tumour Repository Network
- Canadian Institutes for Health Research (CIHR) Foundation grant
- Discovery Frontiers: Advancing Big Data Science in Genomics Research program [RGPGR/448167-2013]
- Natural Sciences and Engineering Research Council of Canada
- Canadian Institutes of Health Research
- Genome Canada
- Canada Foundation for Innovation
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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