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Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers

Kuchenbaecker, Karoline B.; McGuffog, Lesley; Barrowdale, Daniel; Lee, Andrew; Soucy, Penny; Dennis, Joe; Domchek, Susan M.; Robson, Mark; Spurdle, Amanda B. and Ramus, Susan J., et al. (2017) In Journal of the National Cancer Institute 109(7).
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,... (More)

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.

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Journal of the National Cancer Institute
volume
109
issue
7
publisher
Oxford University Press
external identifiers
  • scopus:85016213460
ISSN
0027-8874
DOI
10.1093/jnci/djw302
language
English
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2588ef81-ed7e-4640-84a3-36692e54036b
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2018-09-03 15:27:20
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2018-10-21 04:57:54
@article{2588ef81-ed7e-4640-84a3-36692e54036b,
  abstract     = {<p>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<sup>-53</sup>). 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<sup>-20</sup>). 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.</p>},
  author       = {Kuchenbaecker, Karoline B. and McGuffog, Lesley and Barrowdale, Daniel and Lee, Andrew and Soucy, Penny and Dennis, Joe and Domchek, Susan M. and Robson, Mark and Spurdle, Amanda B. and Ramus, Susan J. and Mavaddat, Nasim and Terry, Mary Beth and Neuhausen, Susan L. and Schmutzler, Rita Katharina and Simard, Jacques and Pharoah, Paul D.P. and Offit, Kenneth and Couch, Fergus J. and Chenevix-Trench, Georgia and Easton, Douglas F. and Antoniou, Antonis C. and Healey, Sue and Lush, Michael and Hamann, Ute and Southey, Melissa and John, Esther M. and Chung, Wendy K. and Daly, Mary B. and Buys, Saundra S. and Goldgar, David E. and Dorfling, Cecilia M. and van Rensburg, Elizabeth J. and Ding, Yuan Chun and Ejlertsen, Bent and Gerdes, Anne Marie and Hansen, Thomas V.O. and Slager, Susan and Hallberg, Emily and Benitez, Javier and Osorio, Ana and Cohen, Nancy and Lawler, William and Weitzel, Jeffrey N. and Peterlongo, Paolo and Pensotti, Valeria and Dolcetti, Riccardo and Barile, Monica and Bonanni, Bernardo and Borg, Ake and Ehrencrona, Hans},
  issn         = {0027-8874},
  language     = {eng},
  month        = {07},
  number       = {7},
  publisher    = {Oxford University Press},
  series       = {Journal of the National Cancer Institute},
  title        = {Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers},
  url          = {http://dx.doi.org/10.1093/jnci/djw302},
  volume       = {109},
  year         = {2017},
}