Abstract
PURPOSE: The risk of subsequent breast cancer among female childhood cancer survivors is markedly elevated. We aimed to determine genetic contributions to this risk, focusing on polygenic determinants implicated in breast cancer susceptibility in the general population. EXPERIMENTAL DESIGN: Whole-genome sequencing (30×) was performed on survivors in the St Jude Lifetime Cohort, and germline mutations in breast cancer predisposition genes were classified for pathogenicity. A polygenic risk score (PRS) was constructed for each survivor using 170 established common risk variants. Relative rate (RR) and 95% confidence interval (95% CI) of subsequent breast cancer incidence were estimated using multivariable piecewise exponential regression. RESULTS: The analysis included 1,133 female survivors of European ancestry (median age at last follow-up = 35.4 years; range, 8.4-67.4), of whom 47 were diagnosed with one or more subsequent breast cancers (median age at subsequent breast cancer = 40.3 years; range, 24.5-53.0). Adjusting for attained age, age at primary diagnosis, chest irradiation, doses of alkylating agents and anthracyclines, and genotype eigenvectors, RRs for survivors with PRS in the highest versus lowest quintiles were 2.7 (95% CI, 1.0-7.3), 3.0 (95% CI, 1.1-8.1), and 2.4 (95% CI, 0.1-81.1) for all survivors and survivors with and without chest irradiation, respectively. Similar associations were observed after excluding carriers of pathogenic/likely pathogenic mutations in breast cancer predisposition genes. Notably, the PRS was associated with the subsequent breast cancer rate under the age of 45 years (RR = 3.2; 95% CI, 1.2-8.3). CONCLUSIONS: Genetic profiles comprised of small-effect common variants and large-effect predisposing mutations can inform personalized breast cancer risk and surveillance/intervention in female childhood cancer survivors.