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

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 ( 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.

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© 2021 by American Society of Clinical Oncology.

Déclaration de conflit d'intérêts

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/authors/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Talia Wegman-OstroskyTravel, Accommodations, Expenses: PfizerDonald A. BarkauskasEmployment: Genentech Stock and Other Ownership Interests: Genentech Patents, Royalties, Other Intellectual Property: U.S. patent based on Ph.D. research in glioblastomaLuke D. MaeseHonoraria: Jazz Pharmaceuticals Consulting or Advisory Role: Jazz PharmaceuticalsSean V. TavtigianPatents, Royalties, Other Intellectual Property: I hold patents on BRCA1, BRCA2, and PTEN. However, the claims in these patents related to genetic testing have been overturned by the US Supreme Court. Continuing claims are irrelevant to the paper. My royalty stream ended more than 2 years ago.Anna GoldenbergResearch Funding: 4UandMeDouglas S. HawkinsResearch Funding: Loxo, Bristol-Myers Squibb, Merck Sharp Dohme, Bayer, Lilly, Eisai, Amgen, Seattle Genetics, Incyte, Jazz Pharmaceuticals Travel, Accommodations, Expenses: Loxo, Bayer, Celgene, AstraZenecaJoshua D. SchiffmanEmployment: PEEL Therapeutics, Inc. Leadership: PEEL Therapeutics, Inc. Stock and Other Ownership Interests: ItRunsInMyFamily.com, PEEL Therapeutics, Inc. Honoraria: Affymetrix Consulting or Advisory Role: N-of-One, Fabric GenomicsJaved KhanResearch Funding: Lentigen Patents, Royalties, Other Intellectual Property: Monoclonal antibody-based therapeutics targeting fibroblast growth factor receptor 4 (FGFR4) for potential treatment of human cancers expressing FGFR4David MalkinConsulting or Advisory Role: Bayer, CanadaDouglas R. StewartEmployment: Genome Medical, LLC No other potential conflicts of interest were reported.