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
breast cancer
cancer patient
cancer risk
cancer susceptibility
gene mutation
genome-wide association study
major clinical study
ovary cancer
population research
priority journal
single nucleotide polymorphism
Breast Neoplasms
genetic predisposition
middle aged
multifactorial inheritance
Ovarian Neoplasms
proportional hazards model
risk assessment
risk factor
statistics and numerical data
tumor suppressor gene
young adult, Adolescent
Genes, BRCA1
Genes, BRCA2
Genetic Predisposition to Disease
Middle Aged
Multifactorial Inheritance
Polymorphism, Single Nucleotide
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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