Nearly Half of <i>TP53</i> Germline Variants Predicted To Be Pathogenic in Patients With Osteosarcoma Are De Novo: A Report From the Children's Oncology Group.

Abstract

To ascertain the prevalence of recurrent de novo variants among 240 pediatric patients with osteosarcoma (OS; age < 20 years) unselected for family history of cancer. The identification of de novo variants was implemented in 2 phases. In the first, we identified genes with a rare (minor allele frequency < 0.01) de novo variant in > 1 of the 95 case-parent trios examined by whole-exome sequencing (WES) who passed quality control measures. In phase 2, 145 additional patients with OS were evaluated by targeted sequencing to identify rare de novo variants in genes nominated from phase 1. Recurrent rare variants identified from phase 1 and 2 were verified as either de novo or inherited by Sanger sequencing of affected patients and their parents. Categorical and continuous data were analyzed using Fisher exact test and t tests, respectively. Among 95 case-parent trios who underwent WES, we observed 61 de novo variants in 60 genes among 47 patients, with <i>TP53</i> identified as the only gene with a pathogenic or likely pathogenic (P/LP) de novo variant in more than one case-parent trio. Among all 240 patients with OS, 13 (5.4%) harbored a P/LP <i>TP53</i> germline variant, of which 6 (46.2%) were confirmed to be de novo. Apart from <i>TP53</i>, we did not observe any other recurrent de novo P/LP variants in the case-parent trios, suggesting that new mutations in other genes are not a frequent cause of pediatric OS. That nearly half of P/LP <i>TP53</i> variants in our sample were de novo suggests universal screening for germline <i>TP53</i> P/LP variants among pediatric patients with OS should be considered.