Abstract
Most gene-environmental studies have focused on breast cancers generally, the preponderance of which occur after age 50. Young-onset breast cancers (YOBC) tend to be aggressive and may be etiologically different. The goal of this analysis was to assess interactions between an established 77-SNP polygenic risk score (PRS) and non-genetic risk factors for YOBC. We constructed the PRS using a family-based study of 1,291 women diagnosed with breast cancer before age 50 and their parents and unaffected sisters. We used conditional logistic regression to analyze interactions between the PRS and 14 established risk factors. In further analyses we assessed the same interactions, but for invasive cancer, estrogen receptor (ER) positive cancer and with broader inclusion of racial/ethnic groups. Results showed a decreased association between the PRS and YOBC risk for women who had ever used hormonal birth control (odds ratio [OR] = 2.20 versus 3.89) and a stronger association between the PRS and YOBC risk in pre-menopausal women (OR = 2.46 versus 1.23). Restricting the analysis to ER+ cancers or invasive cancers or using samples from all ethnic groups produced similar results. In conclusion, the PRS may interact with hormonal birth control use and with menopausal status on risk of YOBC.
Highlights
Gene-environment interactions can be important to identify, both because they offer clues about etiology and because they can help us build algorithms through which we can distinguish high risk from low risk women and devise more personalized screening plans based on well-informed risk assessment
Even though these SNPs were genome-wide association study (GWAS) hits mainly for older onset breast cancer, we have shown previously that many of them were associated with young-onset breast cancer[3] and the 77-SNP polygenic risk score (PRS) is a reasonable measure for young-onset breast cancer
The positive association between PRS and breast cancer risk was lower for women who had ever used hormonal birth control, where ROR is the ratio of odds ratios of PRS in the exposed group divided by that in the unexposed group
Summary
Gene-environment interactions can be important to identify, both because they offer clues about etiology and because they can help us build algorithms through which we can distinguish high risk from low risk women and devise more personalized screening plans based on well-informed risk assessment. Gene-environment interaction effects for overall breast cancer have been assessed by a number of studies, most focusing on the established genetic and reproductive/behavioral risk factors. Rudolph et al studied interactions between the 77-SNP polygenic risk score (PRS) that was originally proposed by Mavaddat[16] and 7 epidemiological factors, using data from the Breast Cancer Association Consortium, and identified interaction between PRS and alcohol consumption, height and hormone therapy[17]. Case-control studies of gene-by-environment interaction can be vulnerable to exposure-related population stratification if the source population includes subpopulations with differing exposure prevalences, which differ in their LD between genetic markers and causative variants[18]. In this paper we assess interactions between the same 77-SNP PRS3 and 14 established risk factors for breast cancer using data from a family-based genome-wide association study (GWAS) of young-onset (under age 50) breast cancer, the Two Sister Study
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