Pathogenic germline variants in cancer susceptibility genes in children and young adults with rhabdomyosarcoma

Jung Kim, Nicholas Light, Vallijah Subasri, Erin L. Young, Talia Wegman-Ostrosky, Donald A. Barkauskas, David Hall, Philip J. Lupo, Rajesh Patidar, Luke D. Maese, Kristine Jones, Mingyi Wang, Sean V. Tavtigian, Dongjing Wu, Adam Shlien, Frank Telfer, Anna Goldenberg, Stephen X. Skapek, Jun S. Wei, Xinyu WenDaniel Catchpoole, Douglas S. Hawkins, Joshua D. Schiffman, Javed Khan, David Malkin, Douglas R. Stewart

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


PURPOSE Rhabdomyosarcoma (RMS) is the most common pediatric soft-tissue sarcoma and accounts for 3% of all pediatric cancer. In this study, we investigated germline sequence and structural variation in a broad set of genes in two large, independent RMS cohorts. MATERIALS AND METHODS Genome sequencing of the discovery cohort (n = 273) and exome sequencing of the secondary cohort (n = 121) were conducted on germline DNA. Analyses were performed on 130 cancer susceptibility genes (CSG). Pathogenic or likely pathogenic (P/LP) variants were predicted using the American College of Medical Genetics and Genomics (ACMG) criteria. Structural variation and survival analyses were performed on the discovery cohort. RESULTS We found that 6.6%-7.7% of patients with RMS harbored P/LP variants in dominant-acting CSG. An additional approximately 1% have structural variants (ATM, CDKN1C) in CSGs. CSG variants did not influence survival, although there was a significant correlation with an earlier age of tumor onset. There was a nonsignificant excess of P/LP variants in dominant inheritance genes in the patients with FOXO1 fusion-negative RMS patients versus the patients with FOXO1 fusion-positive RMS. We identified pathogenic germline variants in CSGs previously (TP53, NF1, DICER1, mismatch repair genes), rarely (BRCA2, CBL, CHEK2, SMARCA4), or never (FGFR4) reported in RMS. Numerous genes (TP53, BRCA2, mismatch repair) were on the ACMG Secondary Findings 2.0 list. CONCLUSION In two cohorts of patients with RMS, we identified pathogenic germline variants for which genespecific therapies and surveillance guidelines may be beneficial. In families with a proband with an RMS-risk P/ LP variant, genetic counseling and cascade testing should be considered, especially for ACMG Secondary Findings genes and/or with gene-specific surveillance guidelines.

Original languageEnglish (US)
Pages (from-to)75-87
Number of pages13
JournalJCO Precision Oncology
StatePublished - 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


Dive into the research topics of 'Pathogenic germline variants in cancer susceptibility genes in children and young adults with rhabdomyosarcoma'. Together they form a unique fingerprint.

Cite this