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

Kim, J; Light, N; Subasri, V; Young, EL; Wegman-Ostrosky, T; Barkauskas, DA; Hall, D; Lupo, PJ; Patidar, R; Maese, LD; Jones, K; Wang, M; Tavtigian, SV; Wu, D; Shlien, A; Telfer, F; Goldenberg, A; Skapek, SX; Wei, JS; Wen, X; Catchpoole, D; Hawkins, DS; Schiffman, JD; Khan, J; Malkin, D; Stewart, DR

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

Kim, J Light, N Subasri, V Young, EL Wegman-Ostrosky, T Barkauskas, DA Hall, D Lupo, PJ Patidar, R Maese, LD Jones, K Wang, M Tavtigian, SV Wu, D Shlien, A Telfer, F Goldenberg, A Skapek, SX Wei, JS Wen, X Catchpoole, D

Hawkins, DS Schiffman, JD Khan, J Malkin, D Stewart, DR

Permalink

Publisher:: American Society of Clinical Oncology
Publication Type:: Journal Article
Citation:: JCO Precision Oncology, 2021, 5, (5), pp. 75-87
Issue Date:: 2021

Closed Access

	Filename	Description	Size
	po.20.00218.pdf		492.01 kB	Adobe PDF	View/Open

Copyright Clearance Process

Recently Added
In Progress
Closed Access

This item is closed access and not available.

Full metadata record

Field	Value	Language
dc.contributor.author	Kim, J
dc.contributor.author	Light, N
dc.contributor.author	Subasri, V
dc.contributor.author	Young, EL
dc.contributor.author	Wegman-Ostrosky, T
dc.contributor.author	Barkauskas, DA
dc.contributor.author	Hall, D
dc.contributor.author	Lupo, PJ
dc.contributor.author	Patidar, R
dc.contributor.author	Maese, LD
dc.contributor.author	Jones, K
dc.contributor.author	Wang, M
dc.contributor.author	Tavtigian, SV
dc.contributor.author	Wu, D
dc.contributor.author	Shlien, A
dc.contributor.author	Telfer, F
dc.contributor.author	Goldenberg, A
dc.contributor.author	Skapek, SX
dc.contributor.author	Wei, JS
dc.contributor.author	Wen, X
dc.contributor.author	Catchpoole, D https://orcid.org/0000-0001-5836-1413
dc.contributor.author	Hawkins, DS
dc.contributor.author	Schiffman, JD
dc.contributor.author	Khan, J
dc.contributor.author	Malkin, D
dc.contributor.author	Stewart, DR
dc.date.accessioned	2022-05-13T01:46:02Z
dc.date.available	2020-11-06
dc.date.available	2022-05-13T01:46:02Z
dc.date.issued	2021
dc.identifier.citation	JCO Precision Oncology, 2021, 5, (5), pp. 75-87
dc.identifier.issn	2473-4284
dc.identifier.issn	2473-4284
dc.identifier.uri	http://hdl.handle.net/10453/157310
dc.description.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.
dc.format	Electronic-eCollection
dc.language	eng
dc.publisher	American Society of Clinical Oncology
dc.relation.ispartof	JCO Precision Oncology
dc.relation.isbasedon	10.1200/PO.20.00218
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject.mesh	Adolescent
dc.subject.mesh	Child
dc.subject.mesh	Child, Preschool
dc.subject.mesh	Cohort Studies
dc.subject.mesh	Female
dc.subject.mesh	Genetic Predisposition to Disease
dc.subject.mesh	Genetic Variation
dc.subject.mesh	Germ Cells
dc.subject.mesh	Humans
dc.subject.mesh	Infant
dc.subject.mesh	Male
dc.subject.mesh	Rhabdomyosarcoma
dc.subject.mesh	Young Adult
dc.subject.mesh	Adolescent
dc.subject.mesh	Child
dc.subject.mesh	Child, Preschool
dc.subject.mesh	Cohort Studies
dc.subject.mesh	Female
dc.subject.mesh	Genetic Predisposition to Disease
dc.subject.mesh	Genetic Variation
dc.subject.mesh	Germ Cells
dc.subject.mesh	Humans
dc.subject.mesh	Infant
dc.subject.mesh	Male
dc.subject.mesh	Rhabdomyosarcoma
dc.subject.mesh	Young Adult
dc.subject.mesh	Germ Cells
dc.subject.mesh	Humans
dc.subject.mesh	Rhabdomyosarcoma
dc.subject.mesh	Genetic Predisposition to Disease
dc.subject.mesh	Cohort Studies
dc.subject.mesh	Adolescent
dc.subject.mesh	Child
dc.subject.mesh	Child, Preschool
dc.subject.mesh	Infant
dc.subject.mesh	Female
dc.subject.mesh	Male
dc.subject.mesh	Genetic Variation
dc.subject.mesh	Young Adult
dc.title	Pathogenic Germline Variants in Cancer Susceptibility Genes in Children and Young Adults With Rhabdomyosarcoma.
dc.type	Journal Article
utslib.citation.volume	5
utslib.location.activity	United States
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology
utslib.copyright.status	closed_access	*
pubs.consider-herdc	false
dc.date.updated	2022-05-13T01:46:00Z
pubs.issue	5
pubs.publication-status	Published
pubs.volume	5
utslib.citation.issue	5

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.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/157310