Polygenic risk scores, radiation treatment exposures and subsequent cancer risk in childhood cancer survivors

Survivors of childhood cancer are at increased risk for subsequent cancers attributable to the late effects of radiotherapy and other treatment exposures; thus, further understanding of the impact of genetic predisposition on risk is needed. Combining genotype data for 11,220 5-year survivors from the Childhood Cancer Survivor Study and the St Jude Lifetime Cohort, we found that cancer-specific polygenic risk scores (PRSs) derived from general population, genome-wide association study, cancer loci identified survivors of European ancestry at increased risk of subsequent basal cell carcinoma (odds ratio per s.d. of the PRS: OR = 1.37, 95% confidence interval (CI) = 1.29–1.46), female breast cancer (OR = 1.42, 95% CI = 1.27–1.58), thyroid cancer (OR = 1.48, 95% CI = 1.31–1.67), squamous cell carcinoma (OR = 1.20, 95% CI = 1.00–1.44) and melanoma (OR = 1.60, 95% CI = 1.31–1.96); however, the association for colorectal cancer was not significant (OR = 1.19, 95% CI = 0.94–1.52). An investigation of joint associations between PRSs and radiotherapy found more than additive increased risks of basal cell carcinoma, and breast and thyroid cancers. For survivors with radiotherapy exposure, the cumulative incidence of subsequent cancer by age 50 years was increased for those with high versus low PRS. These findings suggest a degree of shared genetic etiology for these malignancy types in the general population and survivors, which remains evident in the context of strong radiotherapy-related risk.