Genetic Risk for Subsequent Neoplasms Among Long-Term Survivors of Childhood Cancer

TLDR

Childhood cancer survivors face an elevated risk of subsequent neoplasms, yet the role of germline genetics remains largely unknown. The study evaluated how pathogenic or likely pathogenic mutations in cancer‑predisposition genes influence subsequent neoplasm risk among survivors. Whole‑genome sequencing at 30× depth was performed on 3,006 survivors from the St Jude Lifetime Cohort, and pathogenicity of 60 autosomal‑dominant cancer‑predisposition genes was classified per ACMG guidelines, with relative risks estimated via multivariable piecewise exponential regression stratified by radiation exposure. Among 3,006 survivors, 1,120 subsequent neoplasms occurred in 439 individuals (14.6%); 5.8% carried P/LP mutations, which were linked to markedly higher rates of breast cancer (RR 13.9) and sarcoma (RR 10.6) in irradiated survivors and to increased overall SN risk (RR 4.7) in nonirradiated survivors, supporting universal genetic counseling and targeted testing.

Abstract

Purpose Childhood cancer survivors are at increased risk of subsequent neoplasms (SNs), but the germline genetic contribution is largely unknown. We assessed the contribution of pathogenic/likely pathogenic (P/LP) mutations in cancer predisposition genes to their SN risk. Patients and Methods Whole-genome sequencing (30-fold) was performed on samples from childhood cancer survivors who were ≥ 5 years since initial cancer diagnosis and participants in the St Jude Lifetime Cohort Study, a retrospective hospital-based study with prospective clinical follow-up. Germline mutations in 60 genes known to be associated with autosomal dominant cancer predisposition syndromes with moderate to high penetrance were classified by their pathogenicity according to the American College of Medical Genetics and Genomics guidelines. Relative rates (RRs) and 95% CIs of SN occurrence by mutation status were estimated using multivariable piecewise exponential regression stratified by radiation exposure. Results Participants were 3,006 survivors (53% male; median age, 35.8 years [range, 7.1 to 69.8 years]; 56% received radiotherapy), 1,120 SNs were diagnosed among 439 survivors (14.6%), and 175 P/LP mutations were identified in 5.8% (95% CI, 5.0% to 6.7%) of survivors. Mutations were associated with significantly increased rates of breast cancer (RR, 13.9; 95% CI, 6.0 to 32.2) and sarcoma (RR, 10.6; 95% CI, 4.3 to 26.3) among irradiated survivors and with increased rates of developing any SN (RR, 4.7; 95% CI, 2.4 to 9.3), breast cancer (RR, 7.7; 95% CI, 2.4 to 24.4), nonmelanoma skin cancer (RR, 11.0; 95% CI, 2.9 to 41.4), and two or more histologically distinct SNs (RR, 18.6; 95% CI, 3.5 to 99.3) among nonirradiated survivors. Conclusion The findings support referral of all survivors for genetic counseling for potential clinical genetic testing, which should be prioritized for nonirradiated survivors with any SN and for those with breast cancer or sarcoma in the field of prior irradiation.