Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers
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Kuchenbaecker , K B , McGuffog , L , Barrowdale , D , Lee , A , Soucy , P , Dennis , J , Domchek , S M , Robson , M , Spurdle , A B , Ramus , S J , Mavaddat , N , Terry , M B , Neuhausen , S L , Schmutzler , R K , Simard , J , Pharoah , P D P , Offit , K , Couch , F J , Chenevix-Trench , G , Easton , D F , Antoniou , A C , Healey , S , Lush , M , Hamann , U , Southey , M , John , E M , Chung , W K , Daly , M B , Buys , S S , Goldgar , D E , Dorfling , C M , van Rensburg , E J , Ding , Y C , Ejlertsen , B , Gerdes , A-M , Hansen , T V O , Slager , S , Hallberg , E , Benitez , J , Osorio , A , Cohen , N , Lawler , W , Weitzel , J N , Peterlongo , P , Pensotti , V , Dolcetti , R , Barile , M , Aittomäki , K , Nevanlinna , H & Rantala , J 2017 , ' Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers ' , Journal of the National Cancer Institute , vol. 109 , no. 7 , djw302 . https://doi.org/10.1093/jnci/djw302
| Title: | Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers |
| Author: | Kuchenbaecker, K.B.; McGuffog, L.; Barrowdale, D.; Lee, Andrew; Soucy, P.; Dennis, J.; Domchek, S.M.; Robson, M.; Spurdle, A.B.; Ramus, S.J.; Mavaddat, N.; Terry, M.B.; Neuhausen, S.L.; Schmutzler, R.K.; Simard, J.; Pharoah, P.D.P.; Offit, K.; Couch, F.J.; Chenevix-Trench, G.; Easton, D.F.; Antoniou, A.C.; Healey, S.; Lush, M.; Hamann, U.; Southey, M.; John, E.M.; Chung, W.K.; Daly, M. B.; Buys, S.S.; Goldgar, D.E.; Dorfling, C.M.; van Rensburg, E.J.; Ding, Y.C.; Ejlertsen, B.; Gerdes, A.-M.; Hansen, T.V.O.; Slager, S.; Hallberg, E.; Benitez, J.; Osorio, A.; Cohen, N.; Lawler, W.; Weitzel, J.N.; Peterlongo, P.; Pensotti, V.; Dolcetti, R.; Barile, M.; Aittomäki, K.; Nevanlinna, H.; Rantala, J. |
| Contributor organization: | Department of Medical and Clinical Genetics Kristiina Aittomäki / Principal Investigator HUS Gynecology and Obstetrics Department of Obstetrics and Gynecology |
| Date: | 2017 |
| Language: | eng |
| Number of pages: | 15 |
| Belongs to series: | Journal of the National Cancer Institute |
| ISSN: | 0027-8874 |
| DOI: | https://doi.org/10.1093/jnci/djw302 |
| URI: | http://hdl.handle.net/10138/299319 |
| Abstract: | 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 × 10-53). InBRCA2 carriers, the strongest association with BC risk was seen for the overall BCPRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2 × 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. © The Author 2017. |
| Subject: |
BRCA1 protein
BRCA2 protein estrogen receptor estrogen receptor, adult age Article breast cancer cancer patient cancer risk cancer susceptibility female gene mutation genome-wide association study human major clinical study ovary cancer population research priority journal single nucleotide polymorphism adolescent Breast Neoplasms genetic predisposition genetics heterozygote metabolism middle aged multifactorial inheritance mutation Ovarian Neoplasms procedures prognosis proportional hazards model risk assessment risk factor statistics and numerical data tumor suppressor gene young adult, Adolescent Adult Female Genes, BRCA1 Genes, BRCA2 Genetic Predisposition to Disease Heterozygote Humans Middle Aged Multifactorial Inheritance Mutation Polymorphism, Single Nucleotide Prognosis Proportional Hazards Models Receptors, Estrogen Risk Assessment Risk Factors Young Adult 3122 Cancers |
| Peer reviewed: | Yes |
| Rights: | cc_by |
| Usage restriction: | openAccess |
| Self-archived version: | publishedVersion |
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