{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T07:55:06Z","timestamp":1793174106785,"version":"4.5.0"},"reference-count":45,"publisher":"American Society of Clinical Oncology (ASCO)","issue":"5","content-domain":{"domain":["ascopubs.org"],"crossmark-restriction":true},"short-container-title":["JCO Precision Oncology"],"published-print":{"date-parts":[[2021,11]]},"abstract":"<jats:sec><jats:title>PURPOSE<\/jats:title><jats:p> 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. <\/jats:p><\/jats:sec><jats:sec><jats:title>MATERIALS AND METHODS<\/jats:title><jats:p> 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. <\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p> 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\u2013negative RMS patients versus the patients with FOXO1 fusion\u2013positive 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. <\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSION<\/jats:title><jats:p> 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. <\/jats:p><\/jats:sec>","DOI":"10.1200\/po.20.00218","type":"journal-article","created":{"date-parts":[[2021,1,11]],"date-time":"2021-01-11T22:08:47Z","timestamp":1610402927000},"page":"75-87","update-policy":"https:\/\/doi.org\/10.1200\/crossmark","source":"Crossref","is-referenced-by-count":41,"title":["Pathogenic Germline Variants in Cancer Susceptibility Genes in Children and Young Adults With Rhabdomyosarcoma"],"prefix":"10.1200","author":[{"given":"Jung","family":"Kim","sequence":"first","affiliation":[{"name":"Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, 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