Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers
Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers
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.
Kuchenbaecker, Karoline
5c78179b-8730-4ad2-b157-6a4227696e4b
McGuffog, Lesley
21522096-38bb-45df-aa56-caf2f27d7254
Barrowdale, Daniel
507bc817-9e80-4ff2-a379-470e0d6ed2c9
Eccles, Diana
5b59bc73-11c9-4cf0-a9d5-7a8e523eee23
July 2017
Kuchenbaecker, Karoline
5c78179b-8730-4ad2-b157-6a4227696e4b
McGuffog, Lesley
21522096-38bb-45df-aa56-caf2f27d7254
Barrowdale, Daniel
507bc817-9e80-4ff2-a379-470e0d6ed2c9
Eccles, Diana
5b59bc73-11c9-4cf0-a9d5-7a8e523eee23
Kuchenbaecker, Karoline, McGuffog, Lesley and Barrowdale, Daniel
,
et al.
(2017)
Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers.
JNCI Journal of the National Cancer Institute, 109 (7), [djw302].
(doi:10.1093/jnci/djw302).
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). 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.
Text
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- Accepted Manuscript
More information
Accepted/In Press date: 29 November 2016
e-pub ahead of print date: 9 March 2017
Published date: July 2017
Organisations:
Cancer Sciences
Identifiers
Local EPrints ID: 403212
URI: http://eprints.soton.ac.uk/id/eprint/403212
ISSN: 0027-8874
PURE UUID: bd93f807-85e0-4852-8f68-daa2a409fa59
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Date deposited: 05 Dec 2016 08:43
Last modified: 16 Mar 2024 02:39
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Contributors
Author:
Karoline Kuchenbaecker
Author:
Lesley McGuffog
Author:
Daniel Barrowdale
Corporate Author: et al.
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