Germline genetic variants and pediatric rhabdomyosarcoma outcomes: a report from the Children's Oncology Group.

Child Humans Genome-Wide Association Study Rhabdomyosarcoma / genetics Rhabdomyosarcoma, Alveolar / genetics Proportional Hazards Models Germ Cells / pathology Ubiquitin-Protein Ligases Mediator Complex / genetics

Journal

Journal of the National Cancer Institute
ISSN: 1460-2105
Titre abrégé: J Natl Cancer Inst
Pays: United States
ID NLM: 7503089

Informations de publication

Date de publication:
08 06 2023
Historique:
received: 28 11 2022
revised: 15 02 2023
accepted: 09 03 2023
pmc-release: 23 03 2024
medline: 9 6 2023
pubmed: 24 3 2023
entrez: 23 3 2023
Statut: ppublish

Résumé

Relative to other pediatric cancers, survival for rhabdomyosarcoma (RMS) has not improved in recent decades, suggesting the need to enhance risk stratification. Therefore, we conducted a genome-wide association study for event-free survival (EFS) and overall survival (OS) to identify genetic variants associated with outcomes in individuals with RMS. The study included 920 individuals with newly diagnosed RMS who were enrolled in Children's Oncology Group protocols. To assess the association of each single nucleotide polymorphism (SNP) with EFS and OS, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) using multivariable Cox proportional hazards models, adjusted for clinical covariates. All statistical tests were two sided. We also performed stratified analyses by histological subtype (alveolar and embryonal RMS) and carried out sensitivity analyses of statistically significant SNPs by PAX3/7-FOXO1 fusion status and genetic ancestry group. We identified that rs17321084 was associated with worse EFS (HR = 2.01, 95% CI = 1.59 to 2.53, P = 5.39 × 10-9) and rs10094840 was associated with worse OS (HR = 1.84, 95% CI = 1.48 to 2.27, P = 2.13 × 10-8). Using publicly available data, we found that rs17321084 lies in a binding region for transcription factors GATA2 and GATA3, and rs10094840 is associated with SPAG1 and RNF19A expression. We also identified that CTNNA3 rs2135732 (HR = 3.75, 95% CI = 2.34 to 5.99, P = 3.54 × 10-8) and MED31 rs74504320 (HR = 3.21, 95% CI = 2.12 to 4.86, P = 3.60 × 10-8) were associated with worse OS among individuals with alveolar RMS. We demonstrated that common germline variants are associated with EFS and OS among individuals with RMS. Additional replication and investigation of these SNP effects may further support their consideration in risk stratification protocols.

Sections du résumé

BACKGROUND
Relative to other pediatric cancers, survival for rhabdomyosarcoma (RMS) has not improved in recent decades, suggesting the need to enhance risk stratification. Therefore, we conducted a genome-wide association study for event-free survival (EFS) and overall survival (OS) to identify genetic variants associated with outcomes in individuals with RMS.
METHODS
The study included 920 individuals with newly diagnosed RMS who were enrolled in Children's Oncology Group protocols. To assess the association of each single nucleotide polymorphism (SNP) with EFS and OS, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) using multivariable Cox proportional hazards models, adjusted for clinical covariates. All statistical tests were two sided. We also performed stratified analyses by histological subtype (alveolar and embryonal RMS) and carried out sensitivity analyses of statistically significant SNPs by PAX3/7-FOXO1 fusion status and genetic ancestry group.
RESULTS
We identified that rs17321084 was associated with worse EFS (HR = 2.01, 95% CI = 1.59 to 2.53, P = 5.39 × 10-9) and rs10094840 was associated with worse OS (HR = 1.84, 95% CI = 1.48 to 2.27, P = 2.13 × 10-8). Using publicly available data, we found that rs17321084 lies in a binding region for transcription factors GATA2 and GATA3, and rs10094840 is associated with SPAG1 and RNF19A expression. We also identified that CTNNA3 rs2135732 (HR = 3.75, 95% CI = 2.34 to 5.99, P = 3.54 × 10-8) and MED31 rs74504320 (HR = 3.21, 95% CI = 2.12 to 4.86, P = 3.60 × 10-8) were associated with worse OS among individuals with alveolar RMS.
CONCLUSIONS
We demonstrated that common germline variants are associated with EFS and OS among individuals with RMS. Additional replication and investigation of these SNP effects may further support their consideration in risk stratification protocols.

Identifiants

DOI: 10.1093/jnci/djad055 PMID: 36951526 PMC: PMC10248851
pubmed: 36951526
pii: 7084780
doi: 10.1093/jnci/djad055
pmc: PMC10248851
doi:

Substances chimiques

RNF19A protein, human EC 2.3.2.27
Ubiquitin-Protein Ligases EC 2.3.2.27
MED31 protein, human 0
Mediator Complex 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

733-741

Subventions

Organisme : NCI NIH HHS
ID : T32 CA190194
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32GM088129
Pays : United States
Organisme : NCI NIH HHS
ID : T32CA190194
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA180899
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA180886
Pays : United States

Informations de copyright

© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

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Auteurs

Bailey A Martin-Giacalone (BA)

Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA.
Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
ORCID: 0000-0003-0758-8487

Melissa A Richard (MA)

Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.

Michael E Scheurer (ME)

Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.

Javed Khan (J)

Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Pagna Sok (P)

Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.

Priya B Shetty (PB)

Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.

Stephen J Chanock (SJ)

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Shengchao Alfred Li (SA)

Frederick National Laboratory for Cancer Research, Frederick, MD, USA.

Meredith Yeager (M)

Frederick National Laboratory for Cancer Research, Frederick, MD, USA.

Deborah A Marquez-Do (DA)

Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.

Donald A Barkauskas (DA)

Department of Population and Public Health Sciences, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
QuadW Childhood Sarcoma Biostatistics and Annotation Office, Children's Oncology Group, Monrovia, CA, USA.
ORCID: 0000-0002-2339-719X

David Hall (D)

QuadW Childhood Sarcoma Biostatistics and Annotation Office, Children's Oncology Group, Monrovia, CA, USA.
ORCID: 0000-0003-1257-2316

Matthew T McEvoy (MT)

Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.

Austin L Brown (AL)

Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.

Aniko Sabo (A)

Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
ORCID: 0000-0002-9667-8072

Paul Scheet (P)

Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Chad D Huff (CD)

Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Stephen X Skapek (SX)

Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Douglas S Hawkins (DS)

Division of Hematology-Oncology, Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA, USA.
ORCID: 0000-0003-3602-1375

Rajkumar Venkatramani (R)

Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.

Lisa Mirabello (L)

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MA, USA.

Philip J Lupo (PJ)

Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
ORCID: 0000-0003-0978-5863

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Enfant › Germline genetic variants and pediatric...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Germline genetic variants and pediatric...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Épidémiologie moléculaire › Étude d'association pangénomique › Germline genetic variants and pediatric...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs du tissu conjonctif et des tissus mous › Sarcomes › Myosarcome › Rhabdomyosarcome › Germline genetic variants and pediatric...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs du tissu conjonctif et des tissus mous › Sarcomes › Myosarcome › Rhabdomyosarcome › Rhabdomyosarcome alvéolaire › Germline genetic variants and pediatric...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Statistiques comme sujet › Analyse de survie › Modèles des risques proportionnels › Germline genetic variants and pediatric...
questionsmedicales.fr › Cellules › Cellules germinales › Germline genetic variants and pediatric...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Ligases › Ubiquitin-protein ligase complexes › Ubiquitin-protein ligases › Germline genetic variants and pediatric...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines nucléaires › Complexe médiateur › Germline genetic variants and pediatric...