Abstract 6155: Germline variants in cancer susceptibility genes and subsequent neoplasm risks after childhood cancer: A pooled analysis of two large-scale cohorts

Abstract Background: Increasing evidence suggests germline genetic susceptibility influences the risk of developing subsequent neoplasms (SNs) —a major cause of morbidity and mortality—among childhood cancer survivors, but studies have been hampered by sample size and limited gene sets. We pooled two large-scale cohorts of childhood cancer survivors to characterize overall and specific SN risks among individuals carrying germline variants in 88 known cancer susceptibility genes with an autosomal dominant inheritance pattern. Methods: Using whole-genome or whole-exome sequencing data from the Childhood Cancer Survivor Study and St. Jude Lifetime Cohort (median interquartile range follow-up, 29. 7 13. 8 years), we identified rare, potentially protein-damaging germline variants with SnpEff/ClinVar. Conditional logistic regression evaluated overall SN and SN-specific risk, with up to 100 SN-free controls matched to cases by age, sex, primary childhood cancer type, SN type, radiation dose, chemotherapy, study, and follow-up time. Results: Among 11840 individuals (50. 6% female) who survived childhood cancer, 2162 (18. 3%) developed at least one SN. The risk of developing any SN was elevated among 288 survivors carrying rare, potentially protein-damaging germline variants in an autosomal dominant cancer susceptibility gene (cases=13. 3%; controls=9. 6%; odds ratio OR, 1. 48; 95% confidence interval CI, 1. 30-1. 70; P=5. 12x10-5). A similar proportion of carriers was observed among those who developed common SNs such as basal cell carcinoma (N=107/882, 12. 1%), meningioma (N=52/373, 13. 9%), breast cancer (N=49/353, 13. 9%), and thyroid cancer (N=32/243, 13. 2%). Higher frequencies of carriers were observed in less common SNs, specifically sarcoma (N=24/151, 15. 9%), colorectal cancer (N=15/72, 20. 8%), and glioma (N=16/64, 25. 0%). The observed associations were generally consistent regardless of treatment type for first primary childhood cancer. Gene-specific analyses revealed that the risk of developing any SN was most pronounced among individuals carrying variants in TP53 (cases=0. 6%; controls=0. 04%; OR, 9. 93; 95% CI, 4. 62-21. 34; P=0. 001) and FANCM (cases=0. 9%; controls=0. 5%; OR, 2. 45; 95% CI, 1. 48-4. 03; P=0. 018). Conclusion: In large-scale cohorts of childhood cancer survivors with long-term follow-up, individuals carrying potentially protein-damaging germline variants in known autosomal dominant cancer susceptibility genes have substantially increased SN risk, emphasizing the importance of genetic testing and consideration of genetic risk in follow-up guidelines. However, these individuals account for a small fraction of all SN cases, warranting future research on underlying risk factors in this population. Citation Format: Shahriar A. Zamani, Danielle M. Karyadi, Stephen W. Hartley, Joshua N. Sampson, Todd Gibson, Peter Kraft, Stephen J. Chanock, Lindsay M. Morton. Germline variants in cancer susceptibility genes and subsequent neoplasm risks after childhood cancer: A pooled analysis of two large-scale cohorts abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 6155.