The impact of genetic ancestry on survival outcomes in pediatric rhabdomyosarcoma: A report from the Children’s Oncology Group

Onwuka EA, Magyar CL, Martin-Giacalone BA, Scheurer ME, Marquez-Do DA, Zobeck M, Atkinson EG, Rudzinski ER, Arnold MA, Barkauskas DA, Hall D, Khan J, Shern JF, Scheet P, Crompton B, Linardic CM, Hawkins DS, Venkatramani R, Mirabello L, Huff CD, Richard MA, Lupo PJ. The impact of genetic ancestry on survival outcomes in pediatric rhabdomyosarcoma: A report from the Children’s Oncology Group. HGG Adv. 2025 Jul 10;6(3):100466. doi: 10.1016/j.xhgg.2025.100466. Epub 2025 Jun 9. PMID: 40495382; PMCID: PMC12256324.

Emerging evidence suggests genetic ancestry may influence childhood cancer outcomes, but its impact on pediatric rhabdomyosarcoma (RMS) is unknown. We explored genetic ancestry’s impact on survival among children with RMS. This multi-center observational cohort study is a secondary analysis of previously collected biobanking, genomic, and clinical data. The study included 920 individuals with newly diagnosed RMS under 40 years of age enrolled from 2005 to 2017 under the COG soft tissue sarcoma biobanking protocol D9902. The primary endpoints were (1) event-free survival (EFS), defined as the time from study enrollment to tumor recurrence/progression, secondary malignancy, or death from any cause; and (2) overall survival (OS), defined as the time from study enrollment to death from any cause. Genetic ancestry was estimated using Grafpop software, and Cox regression assessed the association between genetic ancestry and EFS and OS, considering RMS overall, by fusion status, and by histological subtype. Covariates included sex, age at diagnosis, tumor stage, and histology, except during stratified analyses. In embryonal RMS and PAX3/7:FOXO1 fusion-negative RMS, individuals with South Asian or Asian-Pacific Islander ancestry showed worse EFS (hazard ratio [HR] 2.06, 95% confidence interval [CI] 1.07–3.97, p = 0.03 and HR 2.01, 95% CI 1.07–3.76, p = 0.03, respectively) and OS (HR 2.30, 95% CI 1.09–4.84, p = 0.03 and HR 2.33, 95% CI 1.15–4.70, p = 0.020, respectively) compared to those with primarily European genetic ancestry. These findings suggest that genetic ancestry influences survival outcomes within RMS subtypes, and further understanding may improve precision-medicine-based efforts.