TY - JOUR
T1 - Pathogenic germline variants in cancer susceptibility genes in children and young adults with rhabdomyosarcoma
AU - Kim, Jung
AU - Light, Nicholas
AU - Subasri, Vallijah
AU - Young, Erin L.
AU - Wegman-Ostrosky, Talia
AU - Barkauskas, Donald A.
AU - Hall, David
AU - Lupo, Philip J.
AU - Patidar, Rajesh
AU - Maese, Luke D.
AU - Jones, Kristine
AU - Wang, Mingyi
AU - Tavtigian, Sean V.
AU - Wu, Dongjing
AU - Shlien, Adam
AU - Telfer, Frank
AU - Goldenberg, Anna
AU - Skapek, Stephen X.
AU - Wei, Jun S.
AU - Wen, Xinyu
AU - Catchpoole, Daniel
AU - Hawkins, Douglas S.
AU - Schiffman, Joshua D.
AU - Khan, Javed
AU - Malkin, David
AU - Stewart, Douglas R.
N1 - Funding Information:
(1081) (D.M.) and NCTN Operations Center Grant U10 CA180886, Human Specimen Banking Grants U24 CA114766 and 1U24-CA196173, and NCTN Statistics & Data Center Grants U10 CA 180899 and U10 CA098413 of the Children’s Oncology Group and Children’s Oncology Group Chair’s Grant U10 CA098543 from the National Cancer Institute of the National Institutes of Health. Additional research support was provided by a grant from the WWWW (QuadW) Foundation, Inc (www.QuadW.org) to the Children’s Oncology Group. COG ARST0531 was also supported by St. Baldrick’s Foundation. Support was also provided in part through the Cancer Prevention and Research Institute of Texas grant RP170071 (P.L.). JDS is supported by Hyundai Hope on Wheels, Soccer for Hope Foundation, Li-Fraumeni Syndrome Association, Kneaders Bakery & Café Hope Campaign, 5 For The Fight (Qualtrics), and the Elephant p53 (EP53) Program funded through Huntsman Cancer Institute by the State of Utah. N.L. was supported in part from the University of Toronto MD/PhD program, the McLaughlin Center, a Ruggles Family Innovation Award, and a CIHR MD/PhD Studentship; V.S. was supported in part from the Ontario Graduate Scholarship, MBP Excellence Scholarship, and a Vector Institute Research Grant; T.W.-O. was supported in part by CONACYT. This work used the computational resources of the NIH High Performance Computing Biowulf cluster.
Funding Information:
Supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute, Bethesda, MD, a Foundation scheme grant (143234) from the Canadian Institutes for Health Research and a Terry Fox New Frontiers Program Project Grant
Publisher Copyright:
© 2021 by American Society of Clinical Oncology.
PY - 2021
Y1 - 2021
N2 - 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 genespecific 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.
AB - 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 genespecific 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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U2 - 10.1200/PO.20.00218
DO - 10.1200/PO.20.00218
M3 - Article
C2 - 34095712
AN - SCOPUS:85110625863
VL - 5
SP - 75
EP - 87
JO - JCO Precision Oncology
JF - JCO Precision Oncology
SN - 2473-4284
ER -