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

Diessner BJ, Pankratz N, Hooten AJ, Mirabello L, Sarver AL, Mills LJ, Malkin D, Kelley AC, Spector LG. 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. JCO Precis Oncol. 2020;4. doi: 10.1200/PO.20.00087. eCollection 2020. PubMed PMID: 33163847; PubMed Central PMCID: PMC7608506.

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.