Journal
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE
Volume 109, Issue 7, Pages -Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/jnci/djw302
Keywords
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Categories
Funding
- Cancer Research-UK [C12292/A11174, C12292/A20861]
- European Community [223175]
- Cancer Research UK [C12292/A11174, C12292/A20861, C1287/A10118, C1287/A 10710, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/ A16565]
- National Institutes of Health [CA128978]
- Post-Cancer GWAS initiative [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]
- Department of Defence [W81XWH-10-1-0341]
- Canadian Institutes of Health Research (CIHR)
- Komen Foundation for the Cure
- Breast Cancer Research Foundation
- Ovarian Cancer Research Fund [R01-CA122443, P50-CA136393]
- National Cancer Institute [UM1 CA164920]
- Lithuania (BFBOCC-LT): Research Council of Lithuania [LIG-07/2012]
- Cancer Association of South Africa (CANSA)
- Morris and Horowitz Familes Endowed Professorship
- Spanish Association against Cancer (AECC) [RTICC 06/0020/1060, FISPI08/1120]
- Mutua Madrilena Foundation (FMMA)
- City of Hope Clinical Cancer Genetics Community Network
- Hereditary Cancer Research Registry
- Office of the Director, National Institutes of Health
- Fondazione IRCCS Istituto Nazionale Tumori
- National Health and Medical Research Council (NHMRC) Program
- European Union
- Greek national funds through the Operational Program Education and Lifelong Learning of the National Strategic Reference Framework (NSRF) Research Funding Program of the General Secretariat for Research and Technology [SYN11_10_19 NBCA]
- DKFZ
- National Institute for Health Research (NIHR)
- University of Kansas Cancer Center [P30 CA168524]
- Kansas Bioscience Authority Eminent Scholar Program
- Chancellors Distinguished Chair in Biomedical Sciences Professorship
- German Cancer Aid [109076]
- Center for Molecular Medicine Cologne (CMMC)
- Ligue Nationale Contre le Cancer
- Association Le cancer du sein, parlons-en! Award
- Canadian Institutes of Health Research for the CIHR Team in Familial Risks of Breast Cancer program
- French National Institute of Cancer (INCa)
- Non-Therapeutic Subject Registry Shared Resource at Georgetown University (National Institutes of Health [NIH]/National Cancer Institute [NCI] [P30-CA051008]
- Fisher Center for Familial Cancer Research
- Swing For the Cure
- ISCIII (Spain) [RD12/0036/0006, 12/00539]
- Helsinki University Hospital Research Fund, Academy of Finland [266528]
- Finnish Cancer Society
- Sigrid Juselius Foundation
- Dutch Cancer Society [NKI1998-1854, NKI20043088, NKI2007-3756]
- Netherlands Organization of Scientific Research [NWO 91109024]
- Pink Ribbon grant [110005]
- BBMRI [NWO 184.021.007/CP46]
- Hungarian Research grants [KTIA-OTKA CK-80745, OTKA K-112228]
- Norwegian EEA Financial Mechanism [Hu0115/NA/2008-3/ OP-9]
- Asociacion Espanola Contra el Cancer, Spanish Health Research Fund
- Carlos III Health Institute
- Catalan Health Institute and Autonomous Government of Catalonia [ISCIIIRETIC RD06/0020/1051, RD12/0036/008, PI10/01422, PI10/00748, PI13/00285, PIE13/00022, 2009SGR290, 2014SGR364]
- Icelandic Association Walking for Breast Cancer Research
- Landspitali University Hospital Research Fund
- Canadian Breast Cancer Research Alliance [019511]
- Ministry of Economic Development, Innovation and Export Trade [PSR-SIIRI-701]
- Ministero della Salute
- Istituto Oncologico Veneto grant
- Liga Portuguesa Contra o Cancro
- National Breast Cancer Foundation
- National RAMP
- D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea [1020350]
- NIH [CA128978, CA116167, CA176785]
- National Cancer Institute (NCI) Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]
- MH CZ-DRO (MMCI) [00209805]
- European Regional Development Fund
- State Budget of the Czech Republic (RECAMO) [CZ. 1.05/2.1.00/03.0101]
- Charles University in Prague [UNCE204024]
- Robert and Kate Niehaus Clinical Cancer Genetics Initiative
- Andrew Sabin Research Fund [1R01 CA149429-01]
- US National Cancer Institute, NIH
- Russian Federation for Basic Research [14-04-93959, 1504- 01744]
- NRG Oncology Statistical and Data Center [CA 37517]
- NRG Oncology's Cancer Prevention and Control Committee [CA 101165]
- Ohio State University Comprehensive Cancer Center
- ITT (Istituto Toscano Tumori)
- Ministry of Science, Technology and Innovation, Ministry of Higher Education [UM. C/HlR/MOHE/06]
- Cancer Research Initiatives Foundation
- Israel cancer association
- Israeli Inherited breast cancer consortium
- NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA125183, R01 CA142996, 1U01CA161032]
- Ralph and Marion Falk Medical Research Trust
- Entertainment Industry Fund National Women's Cancer Research Alliance
- CRUK
- National Institutes of Health (NIH) [R01-CA102776, R01-CA083855]
- Cancer Center Support Grant from the National Cancer Institute [P30 CA014089]
- American Cancer Society Early Detection Professorship [SIOP-06-258-01COUN]
- National Center for Advancing Translational Sciences (NCATS) [UL1TR000124]
- [SAF2010-20493]
- [5U01CA113916]
- [R01CA140323]
- [PBZ_ KBN_ 122/P05/2004]
- [NO2-CP-11019-50]
- [N02-CP-65504]
- Cancer Research UK [10118, 20861, 17528, 23382, 16561, 15007] Funding Source: researchfish
- Cancer Research UK
- The Francis Crick Institute [10124] Funding Source: researchfish
- National Breast Cancer Foundation [IF-12-06] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0510-10096] Funding Source: researchfish
- Korea Health Promotion Institute [1020350] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2 x 10(53)). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2 x 10(-20)). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management.
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