Somatic and Germline <i>TP53</i> Alterations in Second Malignant Neoplasms from Pediatric Cancer Survivors.

Abstract

<b>Purpose:</b> 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.<b>Experimental Design:</b> 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 <i>TP53</i> variants in SMNs, Sanger sequencing was performed to analyze germline <i>TP53</i> 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.<b>Results:</b> WES revealed <i>TP53</i> mutations involving p53's DNA-binding domain in both index cases, one of which was also present in the germline. The germline and somatic <i>TP53-</i>mutant variants were enriched in the transcriptomes for both sarcomas. Analysis of <i>TP53-</i>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 <i>TP53</i> variant.<b>Conclusions:</b> Currently, germline <i>TP53</i> is not routinely assessed in patients with pediatric cancer. These data support the concept that identifying germline <i>TP53</i> 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. <i>Clin Cancer Res; 23(7); 1852-61. ©2016 AACR</i>.