{"doi":"10.1200/po.20.00218","title":"Pathogenic Germline Variants in Cancer Susceptibility Genes in Children and Young Adults With Rhabdomyosarcoma","abstract":"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.","journal":"JCO Precision Oncology","year":2021,"id":162644,"datarank":1.2672236541517887,"base_score":3.828641396489095,"endowment":3.828641396489095,"self_citation_contribution":0.5742962094733643,"citation_network_contribution":0.6929274446784245,"self_endowment_contribution":0.5742962094733643,"citer_contribution":0.6929274446784245,"corpus_percentile":83.76266728552642,"corpus_rank":2100,"citation_count":45,"citer_count":32,"citers_with_citation_signal":26,"citers_with_endowment":26,"datacite_reuse_total":0,"is_dataset":true,"is_dataset_confidence":0.5633,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":680192,"name":"Nicholas Light","orcid":"0000-0003-2021-3938","position":1,"is_corresponding":false},{"id":680193,"name":"Vallijah Subasri","orcid":"0000-0002-6584-877X","position":2,"is_corresponding":false},{"id":388210,"name":"Erin L. Young","orcid":"0000-0002-7535-006X","position":3,"is_corresponding":false},{"id":54403,"name":"Talía Wegman-Ostrosky","orcid":"0000-0002-3207-6697","position":4,"is_corresponding":false},{"id":277181,"name":"Donald A. Barkauskas","orcid":"0000-0002-2339-719X","position":5,"is_corresponding":false},{"id":277183,"name":"David Hall","orcid":"0000-0003-1257-2316","position":6,"is_corresponding":false},{"id":247448,"name":"Philip J. Lupo","orcid":"0000-0003-0978-5863","position":7,"is_corresponding":false},{"id":680194,"name":"Rajesh Patidar","orcid":"0000-0003-3578-8208","position":8,"is_corresponding":false},{"id":680195,"name":"Luke Maese","orcid":"0000-0002-8739-9100","position":9,"is_corresponding":false},{"id":264023,"name":"Kristine Jones","orcid":"0000-0003-1584-8920","position":10,"is_corresponding":false},{"id":264022,"name":"Mingyi Wang","orcid":"0000-0001-9419-4384","position":11,"is_corresponding":false},{"id":232321,"name":"Sean V. Tavtigian","orcid":"0000-0002-7543-8221","position":12,"is_corresponding":false},{"id":427337,"name":"Dongjing Wu","orcid":null,"position":13,"is_corresponding":false},{"id":393472,"name":"Adam Shlien","orcid":"0000-0002-0368-5370","position":14,"is_corresponding":false},{"id":681108,"name":"Frank Telfer","orcid":null,"position":15,"is_corresponding":false},{"id":12334,"name":"Anna Goldenberg","orcid":"0000-0002-2416-833X","position":16,"is_corresponding":false},{"id":277184,"name":"Stephen X. Skapek","orcid":"0000-0002-4136-8384","position":17,"is_corresponding":false},{"id":250438,"name":"Jun S. Wei","orcid":"0000-0002-4812-0250","position":18,"is_corresponding":false},{"id":648067,"name":"Xinyu Wen","orcid":"0000-0001-8233-5418","position":19,"is_corresponding":false},{"id":111177,"name":"Daniel R. Catchpoole","orcid":"0000-0001-5836-1413","position":20,"is_corresponding":false},{"id":277185,"name":"Douglas S. Hawkins","orcid":"0000-0003-3602-1375","position":21,"is_corresponding":false},{"id":35787,"name":"Joshua D. Schiffman","orcid":"0000-0002-6968-7694","position":22,"is_corresponding":false},{"id":680196,"name":"Javed Khan","orcid":"0000-0002-0120-2814","position":23,"is_corresponding":false},{"id":247632,"name":"David Malkin","orcid":"0000-0001-5752-9763","position":24,"is_corresponding":false},{"id":32693,"name":"Douglas R. Stewart","orcid":"0000-0001-8193-1488","position":25,"is_corresponding":false},{"id":32655,"name":"Jung Kim","orcid":"0000-0001-6274-2841","position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":null,"created_at":"2026-07-18T23:45:05.641178Z","pmid":"34095712","pmcid":"PMC8169077","fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}