Nearly Half of TP53 Germline Variants Predicted To Be Pathogenic in Patients With Osteosarcoma Are De Novo: A Report From the Children’s Oncology Group

Abstract

PURPOSE To ascertain the prevalence of recurrent de novo variants among 240 pediatric patients with oste-osarcoma (OS; age , 20 years) unselected for family history of cancer. METHODS 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. RESULTS Among 95 case-parent trios who underwent WES, we observed 61 de novo variants in 60 genes among 47 patients, with TP53 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 TP53 germline variant, of which 6 (46.2%) were confirmed to be de novo. CONCLUSION Apart from TP53, 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 TP53 variants in our sample were de novo suggests universal screening for germline TP53 P/LP variants among pediatric patients with OS should be considered. INTRODUCTION Osteosarcoma (OS) is the most common primary bone tumor in children and adolescents (age , 20 years) with an age-adjusted incidence of approximately 5.2 cases per million per year. 1 Several inherited cancer predisposition syndromes are associated with an increased risk of OS, 2 including Li-Fraumeni syndrome (LFS), an autosomal dominant disorder caused by pathogenic germline TP53 variants. 3,4 LFS and other inherited syndromes are collectively rare 2,5 ; however, the prevalence of rare pathogenic variants in the OS patient population is reported to be quite substantial. In the largest study to date, 28% of 1,244 patients with OS harbored a pathogenic or likely pathogenic (P/LP) variant in at least one of the 238 cancer-susceptibility genes evaluated. 6 Other smaller studies have reported the prevalence of P/LP cancer-susceptibility gene variants in patients with OS to be between 7.1% (three of 42 patients) 7 and 17.9% (seven of 39 patients), 8 with between 3% and 10% of patients harboring a P/LP variant localized to TP53. 9-11