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. 2023 Jun 8;115(6):733-741.
doi: 10.1093/jnci/djad055.

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

Bailey A Martin-Giacalone  1   2 , Melissa A Richard  2 , Michael E Scheurer  2   3 , Javed Khan  4 , Pagna Sok  2 , Priya B Shetty  2 , Stephen J Chanock  5 , Shengchao Alfred Li  6 , Meredith Yeager  6 , Deborah A Marquez-Do  2 , Donald A Barkauskas  7   8 , David Hall  8 , Matthew T McEvoy  2 , Austin L Brown  2 , Aniko Sabo  9 , Paul Scheet  10 , Chad D Huff  10 , Stephen X Skapek  11 , Douglas S Hawkins  12 , Rajkumar Venkatramani  2 , Lisa Mirabello  13 , Philip J Lupo  2
Affiliations

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

Bailey A Martin-Giacalone et al. J Natl Cancer Inst. .

Abstract

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.

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Conflict of interest statement

The authors have no conflicts of interest to disclose.

Figures

Figure 1.
Figure 1.
Association of common variants with survival outcomes among 920 individuals with rhabdomyosarcoma. Manhattan plots of a genome-wide association study of A) event-free survival and B) overall survival, displaying genome-wide statistically significant single nucleotide polymorphism associations on chromosome 8.
Figure 2.
Figure 2.
Association of single nucleotide variants with event-free survival (EFS) of 920 individuals with rhabdomyosarcoma. Regional association plot displaying linkage disequilibrium (LD) and recombination hotspots for the: A) chr8q24.13 locus, which harbors rs17321084; and B) Kaplan-Meier curve of EFS by genotype (CC, CT, TT) of rs17321084. Regional association plot for the C) chr12p12.1 locus, which harbors rs113830923, and D) Kaplan-Meier curve of EFS by genotype (AA, AG, GG) of rs113830923. Mb = Megabase.
Figure 3.
Figure 3.
Association of single nucleotide variants with overall survival (OS) of 920 individuals with rhabdomyosarcoma. Regional association plot for the A) chr8q22.2 locus, which harbors rs10094840, and B) Kaplan-Meier curve of OS by genotype (GG, GA, AA) of rs10094840. Mb = Megabase.
Figure 4.
Figure 4.
Association of common variants with overall survival (OS) among 268 individuals with alveolar rhabdomyosarcoma. Manhattan plot of a genome-wide association study of OS displaying genome-wide statistically significant single nucleotide polymorphism associations on chromosomes 10 and 17.
Figure 5.
Figure 5.
Association of single nucleotide variants with overall survival (OS) of 268 individuals with alveolar rhabdomyosarcoma. Regional association plot displaying linkage disequilibrium (LD) and recombination hotspots for the A) chr10q21.3 locus, which harbors rs2135732; and B) Kaplan-Meier curve of OS by genotype (GG, AG, or AA) of rs2135732. Individuals with AG or AA genotype were grouped because there was only 1 individual with AA genotype. Regional association plot for the C) chr17p13.1 locus, which harbors rs74504320, and D) Kaplan-Meier curve of OS by genotype (AA, AG, GG) of rs74504320.
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