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

Brandon J. Diessner, Nathan Pankratz, Anthony J. Hooten, Lisa Mirabello, Aaron L. Sarver, Lauren J. Mills, David Malkin, Ava C. Kelley, Logan G. Spector

Research output: Contribution to journalArticlepeer-review

Abstract

PURPOSE 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. 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.

Original languageEnglish (US)
Pages (from-to)1187-1195
Number of pages9
JournalJCO Precision Oncology
Volume4
DOIs
StatePublished - Oct 2 2020

Bibliographical note

Funding Information:
Collection of samples was supported by the Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI; Grant No. U01 CA122371 [L.G.S.]). Sequencing was supported by grants to L.G.S. from Hyundai Hope on Wheels and the Zach Sobiech Osteosarcoma Fund. B.J.D. was supported by a pediatric oncology student training award from the Alex’s Lemonade Stand Foundation and the NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases (Grant No. T32 AR050938 “Musculoskeletal Training Grant”). D.M. was supported by grants from the Canadian Institutes for Health Research and a Program Project from the Terry Fox Research Institute. The Children’s Oncology Group is supported by National Clinical Trials Network (NCTN) Operations Center (Grant No. U10CA180886) and the NCTN Statistics & Data Center (Grant No. U10CA180899).

Funding Information:
Collection of samples was supported by the Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI; Grant No. U01 CA122371 [L.G.S.]). Sequencing was supported by grants to L.G.S. from Hyundai Hope on Wheels and the Zach Sobiech Osteosarcoma Fund. B.J.D. was supported by a pediatric oncology student training award from the Alex?s Lemonade Stand Foundation and the NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases (Grant No. T32 AR050938 ?Musculoskeletal Training Grant?). D.M. was supported by grants from the Canadian Institutes for Health Research and a Program Project from the Terry Fox Research Institute. The Children?s Oncology Group is supported by National Clinical Trials Network (NCTN) Operations Center (Grant No. U10CA180886) and the NCTN Statistics & Data Center (Grant No. U10CA180899). All participants provided informed consent to participate in this research protocol, which was approved by the University of Minnesota Human Research Protection Program (Approval No.: 0701M00961).

Publisher Copyright:
Copyright © 2020 American Society of Clinical Oncology. All rights reserved.

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