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

Wang Z1, Wilson CL1, Easton J1, Thrasher A1, Mulder H1, Liu Q1, Hedges DJ1, Wang S1, Rusch MC1, Edmonson MN1, Levy S1, Lanctot JQ1, Caron E1, Shelton K1, Currie K1, Lear M1, Patel A1, Rosencrance C1, Shao Y1, Vadodaria B1, Yergeau D1, Sapkota Y1, Brooke RJ1, Moon W1, Rampersaud E1, Ma X1, Chang TC1, Rice SV1, Pepper C1, Zhou X1, Chen X1, Chen W1, Jones A1, Boone B1, Ehrhardt MJ1, Krasin MJ1, Howell RM1, Phillips NS1, Lewis C1, Srivastava D1, Pui CH1, Kesserwan CA1, Wu G1, Nichols KE1, Downing JR1, Hudson MM1, Yasui Y1, Robison LL1, Zhang J1.

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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.