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

Autor:	Kim J; Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD., Light N; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.; Institute of Medical Science, University of Toronto, Toronto, ON, Canada., Subasri V; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.; Department of Medical Biophysics, University of Toronto, ON, Canada.; Vector Institute of Artificial Intelligence, Toronto, ON, Canada., Young EL; Department of Pediatrics, University of Utah, Salt Lake City, UT., Wegman-Ostrosky T; Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD.; Basic Research Subdirection, Instituto Nacional de Cancerología (INCan), Mexico City, Mexico., Barkauskas DA; QuadW-COG Childhood Sarcoma Biostatistics and Annotation Office, Children's Oncology Group, Monrovia, CA.; Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA., Hall D; QuadW-COG Childhood Sarcoma Biostatistics and Annotation Office, Children's Oncology Group, Monrovia, CA., Lupo PJ; Department of Pediatrics, Hematology-Oncology Section, Baylor College of Medicine, Houston, TX., Patidar R; Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD., Maese LD; Department of Pediatrics, University of Utah, Salt Lake City, UT., Jones K; Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD., Wang M; Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD., Tavtigian SV; Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT., Wu D; Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD., Shlien A; Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada.; Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, ON, Canada., Telfer F; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.; Department of Medical Biophysics, University of Toronto, ON, Canada., Goldenberg A; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.; Vector Institute of Artificial Intelligence, Toronto, ON, Canada.; Department of Computer Science, University of Toronto, Toronto, ON, Canada., Skapek SX; University of Texas Southwestern, Dallas, TX., Wei JS; Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD., Wen X; Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD., Catchpoole D; The Tumour Bank, Children's Cancer Research Unit, Kids Research Institute, The Children's Hospital at Westmead, Westmead, NSW, Australia., Hawkins DS; Division of Hematology/Oncology, Seattle Children's Hospital, University of Washington, Fred Hutchinson Cancer Research Center, Seattle, WA., Schiffman JD; Department of Pediatrics, University of Utah, Salt Lake City, UT.; Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT., Khan J; Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD., Malkin D; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.; Institute of Medical Science, University of Toronto, Toronto, ON, Canada.; Department of Medical Biophysics, University of Toronto, ON, Canada.; Division of Hematology-Oncology, The Hospital for Sick Children, Department of Pediatrics, University of Toronto, Toronto, ON, Canada., Stewart DR; Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD.
Jazyk:	angličtina
Zdroj:	JCO precision oncology [JCO Precis Oncol] 2021 Jan 11; Vol. 5. Date of Electronic Publication: 2021 Jan 11 (Print Publication: 2021).
DOI:	10.1200/PO.20.00218
Abstrakt:	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. Competing Interests: 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. (© 2021 by American Society of Clinical Oncology.)
Databáze:	MEDLINE
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