Germline Pathogenic/Likely Pathogenic Mutations and Subsequent Neoplasms Among Childhood Cancer Survivors: A Report From the Children's Oncology Group ALTE03N1 Study

PURPOSE – There is emerging evidence that germline pathogenic/likely pathogenic (P/LP) mutations in cancer predisposition genes (CPGs) increase the risk of subsequent neoplasms (SNs) in childhood cancer survivors. However, clinical application of this observation is hampered by the lack of knowledge regarding subpopulations at risk for SNs who could potentially benefit from genetic screening.PATIENTS AND METHODS – Whole-exome sequencing was performed using germline DNA from 499 survivors with SNs (cases) and 625 survivors without (matched controls) in a Children's Oncology Group study. Using conditional logistic regression, we estimated demographic/clinical/therapeutic characteristics and P/LP mutations associated with SN risk. We then randomly partitioned the case-control data set using a 60/40 split to create training and test data, respectively, and developed a clinical risk classifier. Model performance and its improvement with addition of P/LP mutation status was evaluated on the test data using the area under the receiver operating curve (AUC).RESULTS – We found a 4.26-fold higher odds of SNs among P/LP mutation carriers (95% CI, 2.36 to 7.69). The clinical risk classifier (including sex, primary cancer type and year of diagnosis, exposure to radiation and platinum compounds, and length of follow-up) showed a significant performance improvement with the addition of P/LP mutation status, and P/LP × platinum and P/LP × radiation interactions (AUC increased from 0.79 to 0.82, P = .014). Using the clinical risk classifier, we classified survivors at low risk (22%) and moderate-to-high risk (78%) of developing SNs. Overall, 86.4% of the survivors with any P/LP mutations, and all TP53 and RB1 mutation carriers were partitioned into the moderate-to-high risk group.CONCLUSION – These findings provide a risk-based approach for identifying childhood cancer survivors who could be referred for genetic testing, informing surveillance strategies on the basis of refined risk classification.