Pathogenic Germline Variants in Cancer Susceptibility Genes in Children and Young Adults With Rhabdomyosarcoma
| Autor: | Xinyu Wen, David Malkin, Sean V. Tavtigian, Talia Wegman-Ostrosky, Douglas S. Hawkins, Stephen X. Skapek, Erin L. Young, Javed Khan, Anna Goldenberg, Adam Shlien, Luke Maese, Mingyi Wang, Kristine Jones, Rajesh Patidar, Donald A. Barkauskas, Dongjing Wu, Douglas R. Stewart, David Hall, Jun Wei, Vallijah Subasri, Nicholas Light, Jung Kim, Frank Telfer, Joshua D. Schiffman, Daniel Catchpoole, Philip J. Lupo |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male Cancer Research Adolescent Biology Germline Structural variation Cohort Studies 03 medical and health sciences Young Adult 0302 clinical medicine Rhabdomyosarcoma medicine Humans Genetic Predisposition to Disease Young adult Child Gene Genetics Cancer susceptibility Genetic Variation Infant ORIGINAL REPORTS medicine.disease Pediatric cancer 030104 developmental biology Germ Cells Oncology 030220 oncology & carcinogenesis Child Preschool Female Sarcoma |
| Zdroj: | JCO Precis Oncol |
| Popis: | 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 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. |
| Databáze: | OpenAIRE |
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