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 could increase the risk of subsequent neoplasms, but risks for rarer subsequent neoplasms 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 years]) to identify rare deleterious germline variants across 150 literature-based cancer susceptibility genes using the ClinVar (National Library of Medicine) and SnpEff tools. Conditional logistic regression evaluated overall and subsequent neoplasm-specific risk, matching up to 100 subsequent neoplasm-free control individuals to participants by age, sex, childhood cancer type, radiation dose, chemotherapy, study, and follow-up time.

[RESULTS] Among 11 840 survivors, 2165 (18.3%) developed 1 or more subsequent neoplasms. Overall subsequent neoplasm risk was modestly increased for variant carriers in any autosomal dominant cancer susceptibility gene (288/2165 [13.3%] cases; 9.9% of control individuals; odds ratio [OR] = 1.4, 95% CI = 1.3 to 1.6; P = 5.0 × 10-7). Carriers of variants in cancer-specific autosomal dominant cancer susceptibility genes had higher subsequent neoplasm risks, particularly for glioma (OR = 20.4, 95% CI = 7.4 to 56.1; P = 2.7 × 10-10), colorectal cancer (OR = 5.9, 95% CI = 1.4 to 25.7; P = 9.1 × 10-3), bone/soft-tissue sarcoma (OR = 5.3, 95% CI = 2.2 to 12.7; P = 1.5 × 10-3), meningioma (OR = 4.0, 95% CI = 1.4 to 1.0; P = 3.2 × 10-3), basal cell carcinoma (OR = 3.5, 95% CI = 1.2 to 10.0; P = .020), and breast cancer (OR = 2.6, 95% CI = 1.8 to 3.9; P = 2.8 × 10-6), who were also more likely to develop such subsequent neoplasms at younger ages. Notably, all meningioma, sarcoma, and glioma subsequent neoplasms among carriers occurred before ages 20, 25, and 35 years, respectively.

[CONCLUSIONS] Survivors with rare germline variants in cancer-specific autosomal dominant cancer susceptibility genes had increased subsequent neoplasm risk, especially at younger ages. These findings offer a potential basis for enhancing risk-stratified long-term surveillance for childhood cancer survivors.