Somatic and Germline TP53 Alterations in Second Malignant Neoplasms from Pediatric Cancer Survivors

Second malignant neoplasms (SMNs) are severe late complications that occur in pediatric cancer survivors exposed to radiotherapy and other genotoxic treatments. To characterize the mutational landscape of treatment-induced sarcomas and to identify candidate SMN-predisposing variants, we analyzed germline and SMN samples from pediatric cancer survivors. We performed whole-exome sequencing (WES) and RNA sequencing on radiation-induced sarcomas arising from two pediatric cancer survivors. To assess the frequency of germline variants in SMNs, Sanger sequencing was performed to analyze germline in 37 pediatric cancer survivors from the Childhood Cancer Survivor Study (CCSS) without any history of a familial cancer predisposition syndrome but known to have developed SMNs. WES revealed mutations involving p53's DNA-binding domain in both index cases, one of which was also present in the germline. The germline and somatic mutant variants were enriched in the transcriptomes for both sarcomas. Analysis of coding exons in germline specimens from the CCSS survivor cohort identified a G215C variant encoding an R72P amino acid substitution in 6 patients and a synonymous SNP A639G in 4 others, resulting in 10 of 37 evaluable patients (27%) harboring a germline variant. Currently, germline is not routinely assessed in patients with pediatric cancer. These data support the concept that identifying germline variants at the time a primary cancer is diagnosed may identify patients at high risk for SMN development, who could benefit from modified therapeutic strategies and/or intensive posttreatment monitoring. .