Abstract 3257: Polygenic risk score, stage, and mode of detection in relation to breast cancer risk

Abstract

Abstract Identification of increasing numbers of breast cancer risk variants holds promise to improve risk prediction and identify population subgroups that could benefit from targeted prevention and early detection. We aimed to examine whether women with increased polygenic risk are more likely to be diagnosed with symptomatic breast cancer. A case-control study including data collected from interviews, DNA from saliva, and cancer registry data collected between 2001-2007 (4,315 cases, 3,919 controls) was used to construct a polygenic risk score (PRS). Single nucleotide polymorphisms (SNPs, N=98) were selected from recently published genome-wide association studies of breast cancer and breast density, and comparative rat genome studies. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) associated with the SNPs. SNPs with p-values ≤0.10 (N=24) were used to construct quintiles of the PRS by multiplying the log-odds of the SNPs by the number of risk alleles; multivariable logistic regression models evaluated all women and strata of women defined by method of detection and stage at diagnosis. Odds ratios were adjusted for age, family history of breast cancer, age at menopause/menopausal status, body mass index, parity, and age at first birth. Overall, PRS quintile categories were associated with breast cancer risk in a dose response manner (Q1: OR=1, reference; Q2 OR=1.36, 95% CI 1.16-1.58; Q3 OR=1.66, 95% CI 1.43-1.93; Q4 OR=1.83, 95% CI 1.58-2.12; Q5 OR=2.58, 95% CI 2.23-2.98). Evaluated on a continuous scale, the PRS was associated with an OR=1.38 for a 1-unit change in the standard deviation (SD), 95% CI 1.32-1.45. Odds ratios were essentially unchanged when stratified by method of detection (p-value=0.40). The odds ratio of breast cancer associated with the continuous PRS was elevated among women diagnosed with advanced breast cancer: DCIS, OR=1.36, 95% CI 1.26-1.47 per 1 SD; localized OR=1.37, 95% CI 1.30-1.45 per 1 SD; regional OR=1.38, 95% CI 1.28-1.48 per 1 SD; and distant OR=1.82, 95% CI 1.39-2.40. These results suggest that polygenic risk scores are strongly related to breast cancer risk, that the association does not vary by method of breast cancer detection, but that the association is strongest for metastatic breast cancer. Citation Format: Amy Trentham-Dietz, John M. Hampton, Irene M. Ong, C David Page, Michael N. Gould, Jill D. Haag, Polly A. Newcomb, James D. Shull, Elizabeth S. Burnside. Polygenic risk score, stage, and mode of detection in relation to breast cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3257.