Abstract LB333: Homologous recombination germline variants and radiotherapy-related subsequent neoplasm risk after childhood cancer: A pooled analysis in two large cohorts

Abstract Background: Radiotherapy (RT) for childhood cancer substantially increases the risk of subsequent neoplasms (SNs). The Childhood Cancer Survivor Study (CCSS) and the St. Jude Lifetime Cohort Study (SJLIFE) have reported increased risks of SNs among survivors carrying rare variants in homologous recombination repair (HRR) genes. Radiobiological data suggest that DNA damage responses may vary by radiation dose, but the individual studies had limited sample sizes for a comprehensive investigation of SN risks by RT dose exposure. Methods: In a pooled analysis of 12,180 survivors (CCSS=8,339; SJLIFE=3,841), we identified carriers of rare, potentially protein-damaging HRR germline variants (deleterious HRR variants) in 87 pathway genes, annotated using SnpEff and ClinVar. Region-specific RT dose exposure was reconstructed using medical records and categorized into no RT, out-of-field RT (>0 to <10 Gy), and in/near-field RT (≥10 Gy). Conditional logistic regression estimated the association between deleterious HRR variants and RT-related SNs (RT-SNs, with the most common types in the analysis being breast cancer, meningioma, thyroid cancer, and bone or soft-tissue sarcoma, excluding basal cell carcinoma), with up to 100 SN-free controls matched to cases by age, sex, primary childhood cancer type, RT dose to the SN location, chemotherapy, study, and follow-up time. Results: Among all survivors, 1,253 (10.3%) carried deleterious HRR variants, and 1,301 (10.7%) developed ≥1 RT-SNs. Deleterious HRR variants were associated with increased odds of RT-SNs after out-of-field RT exposure (cases, 40/190=21.1%; controls, 9.7%; OR, 2.5; 95% CI, 1.7 to 3.6; P=4.80x10-6), with similar study-specific results (CCSS: OR, 2.5; 95% CI, 1.6 to 3.7; P=3.77x10-5 and SJLIFE: OR, 2.5; 95% CI, 1.0 to 6.4; P=3.07x10-2). No association was observed after in/near-field RT exposure (cases, 87/832=10.5%; controls, 11.7%; P=0.539) or no RT (cases, 22/220=10.0%; controls, 10.2%; P=0.868). In analyses of individual RT-SNs after out-of-field RT exposure, deleterious HRR variants were associated with increased odds of thyroid cancer (OR, 2.4, 95% CI, 1.3 to 4.6) and breast cancer (OR, 2.4; 95% CI, 1.5 to 4.9), while associations with other SN types of >1 case (ORs ranging from 1.3 to 3.5) were not statistically significant. The association between deleterious HRR variants and odds of out-of-field RT-SNs did not follow a pattern by individual genes, though per-gene case counts were few. Conclusion: These findings underscore the importance of HRR genetic variants in conferring susceptibility to RT-SNs, given their vitalness in repairing radiation-induced DNA double-strand breaks. The observed associations suggest that DNA damage repair responses may be modulated by RT dose exposure, highlighting the complex origins of subsequent neoplasms in childhood cancer survivors. Citation Format: Shahriar A. Zamani, Danielle M. Karyadi, Stephen W. Hartley, Joshua N. Sampson, Todd M. Gibson, Peter Kraft, Stephen J. Chanock, Lindsay M. Morton. Homologous recombination germline variants and radiotherapy-related subsequent neoplasm risk after childhood cancer: A pooled analysis in two large cohorts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB333.