Abstract 2567: Genetic risk stratification for breast cancer based on a polygenic risk score and family history.
Authors: Mavaddat Nasim , Pharoah Paul , Hall Per , Easton Douglas , Garcia-Closas Montserrat ,   for the Breast Cancer Association Consortium
Published: August 2014

Abstract
Background: Breast cancer is the most common cancer among Western women. Risk stratification of women can aid surveillance for and prevention of breast cancer. However, the value of genetic profiling in risk stratification has been widely debated. Early studies were based on risk profiles generated from only a few genetic variants, while recent genome-wide association studies (GWAS) have led to the identification of many more loci. We investigated the value of using 77 single nucleotide polymorphisms (SNPs) in breast cancer susceptibility loci identified to date for risk stratification of women both with and without a family history of breast cancer.
Methods: We tested for all possible pair-wise multiplicative SNP interactions between 77 SNPs using 46,450 cases and 42,599 controls of European origin in the Breast Cancer Association Consortium (BCAC) using logistic regression analyses. A subset of 33,673 cases and 33,381 controls from studies not selected for family history was used to construct a polygenic risk score (PRS) based on the 77 SNPs. Estimates of the relative risk for breast cancer by levels of the PRS and population-based breast cancer incidence and mortality rates were used to derive absolute risks of developing breast cancer for percentiles of the PRS.
Results: There was no strong evidence for multiplicative interaction between any particular SNP pair, but there was a suggestion of a larger number of observed significant interactions over those expected by chance. Women in the highest 1% of the PRS score had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (40-60thpctile)(OR=3.36 95%CI:2.95-3.83). The corresponding relative risks for PRSs derived separately for ER-positive and ER-negative disease were 3.73 95%CI:3.24-4.30 and 2.80 95%CI: 2.26-3.46, respectively. The OR for family history (1 or more first degree relatives with breast cancer) was slightly attenuated, from 1.85 to 1.74, after adjusting for the PRS, consistent with the estimated fraction (∼14%) of the familial relative risk explained by the 77 SNPs under a multiplicative polygenetic model of inheritance. The combined effects of PRS and family history of breast cancer were consistent with a multiplicative model (P-interaction=0.34). The 10-year absolute risk of breast cancer for a 50 year old woman without family history of breast cancer ranged from 0.70 % for women in the lowest 1% of the PRS, 2.4% for the middle quintile, to 7.1 % for the highest 1% of the PRS. For a 50 year old woman with a family history, the corresponding risk ranged from 1.2%, 4.0% and 11.2%, respectively.
Conclusion: The PRS provides good discrimination of breast cancer risk across women without a family history of breast cancer, and can also be used to further refine the genetic risk among women with a family history. The observed level of risk discrimination could be useful to inform targeted screening or prevention strategies.
Citation Format: Nasim Mavaddat, Paul Pharoah, Per Hall, Douglas Easton, Montserrat Garcia-Closas, for the Breast Cancer Association Consortium. Genetic risk stratification for breast cancer based on a polygenic risk score and family history. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2567. doi:10.1158/1538-7445.AM2013-2567
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.