Homologous recombination repair germline variants and subsequent neoplasm risk among childhood cancer survivors.

Childhood cancer radiation therapy (RT) increases subsequent neoplasm risk. Radiation dose may modulate DNA damage responses, but the small sample sizes of prior human studies of homologous recombination repair hampered dose-specific investigations. We pooled data for 12 180 survivors (8339 from the Childhood Cancer Survivor Study and 3841 from the St Jude Lifetime Cohort) to estimate associations between deleterious homologous recombination repair variants and RT-related subsequent neoplasms (most commonly breast cancer, meningioma, thyroid cancer, and sarcoma) using conditional logistic regression with matched controls. In all, 1253 (10.3%) survivors were homologous recombination repair variant carriers, and 1301 (10.7%) developed at least 1 RT-related subsequent neoplasms. Variants increased the risk of out-of-field RT-related subsequent neoplasms (cases, 40/190 [21.1%]; control individuals, 9.7%; odds ratio [OR] = 2.5, 95% confidence interval [CI] = 1.7 to 3.6; P = 4.80 ×10-6), with consistent results across cohorts (Childhood Cancer Survivor Study, OR = 2.5, 95% CI = 1.6 to 3.7, P = 3.77 ×10-5; St Jude Lifetime Cohort, OR = 2.5, 95% CI = 1.0 to 6.4, P = 3.07 ×10-2). No association was observed for in-field or near-field subsequent neoplasms or individuals not undergoing RT. Findings emphasize homologous recombination repair variant-conferred susceptibility to RT-related subsequent neoplasms and dose-dependent DNA damage repair.