Jung Kim1, Nicholas Light2,3, Vallijah Subasri2,4,5, Erin L Young6, Talia Wegman-Ostrosky1,7, Donald A Barkauskas8,9, David Hall8, Philip J Lupo10, Rajesh Patidar11, Luke D Maese6, Kristine Jones12, Mingyi Wang12, Sean V Tavtigian13, Dongjing Wu12, Adam Shlien14,15, Frank Telfer2,4, Anna Goldenberg2,5,16, Stephen X Skapek17, Jun S Wei11, Xinyu Wen11, Daniel Catchpoole18, Douglas S Hawkins19, Joshua D Schiffman6,13, Javed Khan11, David Malkin2,3,4,20, Douglas R Stewart1. 1. Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD. 2. Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada. 3. Institute of Medical Science, University of Toronto, Toronto, ON, Canada. 4. Department of Medical Biophysics, University of Toronto, ON, Canada. 5. Vector Institute of Artificial Intelligence, Toronto, ON, Canada. 6. Department of Pediatrics, University of Utah, Salt Lake City, UT. 7. Basic Research Subdirection, Instituto Nacional de Cancerología (INCan), Mexico City, Mexico. 8. QuadW-COG Childhood Sarcoma Biostatistics and Annotation Office, Children's Oncology Group, Monrovia, CA. 9. Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA. 10. Department of Pediatrics, Hematology-Oncology Section, Baylor College of Medicine, Houston, TX. 11. Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD. 12. Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD. 13. Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT. 14. Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada. 15. Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, ON, Canada. 16. Department of Computer Science, University of Toronto, Toronto, ON, Canada. 17. University of Texas Southwestern, Dallas, TX. 18. The Tumour Bank, Children's Cancer Research Unit, Kids Research Institute, The Children's Hospital at Westmead, Westmead, NSW, Australia. 19. Division of Hematology/Oncology, Seattle Children's Hospital, University of Washington, Fred Hutchinson Cancer Research Center, Seattle, WA. 20. Division of Hematology-Oncology, The Hospital for Sick Children, Department of Pediatrics, University of Toronto, Toronto, ON, Canada.
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. 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.
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.
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