Rare Variants Associated With Pediatric Cancer Treatment–Related Second Malignant Neoplasm Risk

PURPOSE Survivors of childhood cancers are at risk of second malignant neoplasms (SMNs). Exposure to radiation therapy and different chemotherapy agents are known risk factors for SMN development. However, there remains interindividual variability that could be attributed to genetic variations. Our study aims to identify rare genetic variants associated with SMN risk and assess the influence of treatment on the associated risk of these variants. MATERIALS AND METHODS We conducted a whole-exome sequencing in a nested case-control study within the French Childhood Cancer Survivors Study for 450 survivors including 163 cases and 287 controls. Rare variants in genes within replication, recombination, and repair pathways were selected. Gene-based association tests were conducted and a logistic regression analysis was used to estimate the effect of selected genes on SMN risk, adjusting for relevant clinical variables. Specific analysis restricted to breast and thyroid SMNs were also performed. Stratified analyses on the basis of the radiation doses received by the bone marrow and specific organs were also conducted. RESULTS We have identified several genetic associations: the RNASEL and APOBEC3F genes (odds ratio [OR], 5.43 [95% CI, 1.76 to 20.44]; P = .0055 and OR, 4.8 [95% CI, 1.28 to 22.95]; P = .027, respectively) are associated with the risk of SMN, while the FANCM gene (OR, 4.65 [95% CI, 1.06 to 21.56]; P = .041) is associated with the risk of developing breast SMN. CONCLUSION This study provides new evidence regarding the involvement of genetics in the development of SMN. Additional research is needed to confirm these results and uncover the underlying mechanisms behind these associations. If replicated, these findings will help identify survivors at higher risk of developing SMN, enabling tailored treatment and follow-up strategies.