Germline rare variants in cancer susceptibility genes and subsequent neoplasm risk after childhood cancer.

BACKGROUND Among childhood cancer survivors, germline rare variants in autosomal dominant cancer susceptibility genes (AD CSGs) could increase subsequent neoplasm (SNs) risks, but risks for rarer SNs and by age at onset are not well understood. METHODS We pooled the Childhood Cancer Survivor Study and St Jude Lifetime Cohort (median follow-up = 29.7 years, range 7.1-55.6) to identify rare deleterious germline variants across 150 literature-based CSGs using ClinVar and SnpEff. Conditional logistic regression evaluated overall and SN-specific risk, matching up to 100 SN-free controls to cases by age, sex, childhood cancer, radiation dose, chemotherapy, study, and follow-up time. RESULTS Among 11,840 survivors, 2,165 (18.3%) developed ≥1 SN. Overall SN risk was modestly increased for variant carriers in any AD CSG (cases = 288/2165, 13.3%, controls = 9.9%; odds ratio, 95% confidence interval: 1.4, 1.3 to 1.6, p = 5.0 × 10-7). Carriers of variants in cancer-specific AD CSGs had higher SN risks, particularly for glioma (20.4, 7.4 to 56.1, p = 2.7 × 10-10), colorectal cancer (5.9, 1.4 to 25.7, p = 9.1 × 10-3), bone/soft-tissue sarcoma (5.3, 2.2 to 12.7, p = 1.5 × 10-3), meningioma (4.0, 1.4 to 1.0, p = 3.2 × 10-3), basal cell carcinoma (3.5, 1.2 to 10.0, p = .020), and breast cancer (2.6, 1.8 to 3.9, p = 2.8 × 10-6), who were also more likely to develop such SNs at younger ages. Notably, all meningioma, sarcoma, and glioma SNs among carriers occurred before ages 20, 25, and 35 years, respectively. CONCLUSIONS Survivors with rare germline variants in cancer-specific AD CSGs had increased SN risk, especially at younger ages. These findings offer a potential basis for enhancing risk-stratified long-term surveillance for childhood cancer survivors.