Pathogenic Germline Variants in Cancer Susceptibility Genes in Children and Young Adults With Rhabdomyosarcoma.

Abstract

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. 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. 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 (<i>ATM</i>, <i>CDKN1C</i>) 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 <i>FOXO1</i> fusion-negative RMS patients versus the patients with <i>FOXO1</i> fusion-positive RMS. We identified pathogenic germline variants in CSGs previously (<i>TP53</i>, <i>NF1</i>, <i>DICER1</i>, mismatch repair genes), rarely (<i>BRCA2</i>, <i>CBL</i>, <i>CHEK2</i>, <i>SMARCA4</i>), or never (<i>FGFR4</i>) reported in RMS. Numerous genes (<i>TP53</i>, <i>BRCA2</i>, mismatch repair) were on the ACMG Secondary Findings 2.0 list. In two cohorts of patients with RMS, we identified pathogenic germline variants for which gene-specific 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.