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

Childhood cancer radiotherapy (RT) increases subsequent neoplasm (SN) risk. Radiation dose may modulate DNA damage responses, but the small sample sizes of prior human studies of homologous recombination repair (HRR) hampered dose-specific investigations. We pooled data for 12,180 survivors (Childhood Cancer Survivor Study [CCSS]=8,339; St. Jude Lifetime Cohort [SJLIFE]=3,841) to estimate associations between deleterious HRR variants and RT-related SNs (RT-SNs, most commonly breast cancer, meningioma, thyroid cancer, and sarcoma) using conditional logistic regression with matched controls. 1,253 (10.3%) survivors were HRR variants carriers and 1,301 (10.7%) developed ≥1 RT-SNs. Variants increased risk of out-of-field RT-SNs (cases, 40/190 = 21.1%; controls, 9.7%; OR, 2.5; 95%CI, 1.7 to 3.6; P = 4.80x10-6), with consistent results across cohorts (CCSS: OR, 2.5; 95%CI, 1.6 to 3.7; P = 3.77x10-5; SJLIFE: OR, 2.5; 95%CI, 1.0 to 6.4; P = 3.07x10-2). No association was observed for in/near-field SNs or those without RT. Findings emphasize HRR variant-conferred susceptibility to RT-SNs and dose-dependent DNA damage repair.