Skip to main content

Germline mutations in DNA repair genes are overrepresented in children and young adults with rhabdomyosarcoma: A discovery and validation cohort study

Wednesday, September 13, 2017 — Poster Session II

3:30 p.m. – 5:00 p.m.
FAES Terrace


  • T Wegman-Ostrosky
  • N Light
  • E Young
  • HC Chen
  • YY Chi
  • D Hall
  • DS Hawkins
  • J Kim
  • PJ Lupo
  • R Patidar
  • A Shlien
  • S Skapek
  • M Tyagi
  • J Wei
  • JD Schiffman
  • J Khan
  • D Malkin
  • DR Stewart


Intro. Rhabdomyosarcoma (RMS) is the most prevalent soft tissue tumor in childhood and adolescents. The etiology of RMS remains largely unknown; it is reported that hereditary factors account for 7-33% of RMS. We sought to determine the prevalence of pathogenic germline mutations in RMS patients. Methods. Germline whole-exome sequencing (WES) was conducted at the NCI on the discovery cohort (n=121); whole-genome sequencing (WGS) was conducted at SickKids on the validation cohort (n=122). WES was performed on 598 cancer-free adult controls from NCI studies. Analysis on 137 cancer-predisposition genes focused on those with dominant inheritance. We reviewed variants with a MAF 20 and evidence of pathogenicity in ClinVar or HGMD-DM (after literature review) were considered likely pathogenic (LP). Results. In the NCI cohort, 12 P/LP variants were identified (10%; P=0.009) in ATM, DICER1, FLCN, MSH6, NF1, PTPN11, RB1, RET, TP53 and SDHA. In the Toronto cohort, 13 P/LP variants were identified (11%; P=0.004) in ATM, BRCA2, CHEK2, EXT2, HRAS, NF1, RB1, RET, and TP53. Genes with P/LP variation common to both cohorts were ATM, NF1, RB1 and TP53. In the controls, there were 23 P/LP variants (4%). Conclusion. We observed a significant excess of pathologic germline variation in RMS in multiple cancer predisposition genes. Our results suggest that germline genetic testing may be of clinical utility for patients with sporadic RMS, and that pathogenetic variants in DNA repair pathway genes may be broadly relevant to the etiology of these cancers.

Category: Genetics and Genomics