Evaluation of Polygenic Risk Scores for Breast and Ovarian Cancer Risk Prediction in BRCA1 and BRCA2 Mutation Carriers.
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Date
2017-07-01ICR Author
Author
Kuchenbaecker, KB
McGuffog, L
Barrowdale, D
Lee, A
Soucy, P
Dennis, J
Domchek, SM
Robson, M
Spurdle, AB
Ramus, SJ
Mavaddat, N
Terry, MB
Neuhausen, SL
Schmutzler, RK
Simard, J
Pharoah, PDP
Offit, K
Couch, FJ
Chenevix-Trench, G
Easton, DF
Antoniou, AC
Type
Journal Article
Metadata
Show full item recordAbstract
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 ). 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 = 7.2×10 -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.
Collections
Subject
Adolescent
Adult
Breast Neoplasms
Female
Genes, BRCA1
Genes, BRCA2
Genetic Predisposition to Disease
Heterozygote
Humans
Middle Aged
Multifactorial Inheritance
Mutation
Ovarian Neoplasms
Polymorphism, Single Nucleotide
Prognosis
Proportional Hazards Models
Receptors, Estrogen
Risk Assessment
Risk Factors
Young Adult
Research team
Oncogenetics
Language
eng
Date accepted
2016-11-16
License start date
2017-07-01
Citation
J Natl Cancer Inst, 2017, 109 (7)