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

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.