Wang Z, et al. - Authors evaluated the contribution of pathogenic/likely pathogenic (P/LP) mutations in cancer predisposition genes to their subsequent neoplasms (SN) risk. As per the data, all survivors should be referred for genetic counseling for potential clinical genetic testing. Experts suggested that this counselling should be prioritized for nonirradiated survivors with any SN and for those with breast cancer or sarcoma in the field of prior irradiation.

Methods

• Experts performed whole-genome sequencing (30-fold) 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.
• They classified the germline mutations in 60 genes known to be related to autosomal dominant cancer predisposition syndromes with moderate to high penetrance by their pathogenicity, according to the American College of Medical Genetics and Genomics guidelines.
• They estimated the relative rates (RRs) and 95% CIs of SN occurrence by mutation status using multivariable piecewise exponential regression stratified by radiation exposure.

Results

• There were 3,006 survivors (53% male; median age, 35.8 years [range, 7.1 to 69.8 years]; 56% received radiotherapy) who participated, and 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.
• Findings suggested an association of mutations 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 2 or more histologically distinct SNs (RR, 18.6; 95% CI, 3.5 to 99.3) among nonirradiated survivors.