Journal
NATURE GENETICS
Volume 52, Issue 6, Pages 572-+Publisher
NATURE RESEARCH
DOI: 10.1038/s41588-020-0609-2
Keywords
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Categories
Funding
- Federal funds from the National Cancer Institute Intramural Research Program, National Institutes of Health
- government of Canada through Genome Canada
- Canadian Institutes of Health Research [GPH-129344]
- Ministere de l'Economie et de la Science et de l'Innovation du Quebec through Genome Quebec
- Quebec Breast Cancer Foundation for the PERSPECTIVE project
- US National Institutes of Health (NIH) [1U19 CA148065, X01HG007492, HHSN268201200008I]
- Cancer Research UK [C1287/A16563, C1287/A10710, C1287/A10118, C12292/A11174, C12292/A20861]
- Odense University Hospital Research Foundation (Denmark)
- National RAMP
- D Program for Cancer Control-Ministry of Health and Welfare (Republic of Korea) [1420190]
- Italian Association for Cancer Research (AIRC) [IG16933]
- Breast Cancer Research Foundation
- National Health and Medical Research Council (Australia)
- German Cancer Aid [110837]
- European Union [HEALTH-F2-2009-223175]
- NIH [CA128978, CA116167, CA176785]
- Post-Cancer GWAS initiative [1U19 CA148065, 1U19 CA148537, 1U19 CA148112]
- NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]
- Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer
- Ministere de l'Economie, Innovation et Exportation du Quebec [PSR-SIIRI-701]
- Komen Foundation for the Cure
- Ovarian Cancer Research Fund
- NIH Cancer Post-Cancer GWAS initiative [1U19 CA148065]
- European Union via its Seventh Framework Programme [HEALTH-F2-2009-223175]
- Horizon 2020 Research and Innovation Programme [633784, 634935]
- NHGRI [1R01 HG010480-01]
- [CA194393]
- National Breast Cancer Foundation [ECF-17-010] Funding Source: researchfish
- Korea Health Promotion Institute [1420190] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- NATIONAL CANCER INSTITUTE [ZIACP010126] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [ZIAES044005, ZIAES102245, ZIAES049033] Funding Source: NIH RePORTER
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Genome-wide analysis identifies 32 loci associated with breast cancer susceptibility, accounting for estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype(1-3). To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 x 10(-8)), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.
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