Genetic Polymorphisms in Apoptosis-Related Genes XAF1 and XIAP Are Associated with Clinical Outcomes in Pediatric Ewing Sarcoma

Background/Objectives: Ewing sarcoma (ES) is an aggressive malignant cancer with a higher incidence in adolescents and young adults. Despite multimodal therapy, prognosis remains poor, particularly in metastatic and recurrence cases. Dysregulation of apoptosis is central to ES tumorigenesis; however, the impact of polymorphisms in apoptotic regulators on clinical outcomes remains unclear. This study investigated the association between single-nucleotide polymorphisms (SNPs) in the apoptotic pathway genes XAF1 and XIAP and their respective protein expression in ES outcomes. Methods: A cross-sectional study was conducted on ES samples from paraffin blocks (n = 55). Genotyping for selected SNPs and immunohistochemistry for XAF1 and XIAP expression were performed. The cohort included 41 pediatric and 14 non-pediatric cases. Statistical associations were analyzed between genotypes, age groups, protein expression, and recurrence. Results: The male sex (61.8%) and bone site (75.5%) were prevalent, while recurrence (30.9%) and metastasis (14.5%) were frequent outcomes. There was low or absent XAF1 expression (<1.2 μm2) in 75.5% of all ES cases, and 54.9% showed higher XIAP expression (≥16.4 μm2). The A allele present in the dominant group (AA + AG) of the rs3785793 [A/G] XAF1 gene, showed significantly lower XAF1 expression (p = 0.043) and was associated with recurrence in comparison to the GG genotype in pediatric ES. Conclusions: ES showed low or absent protein XAF1 expression and high XIAP expression. The wild-type A-allele of XAF1 rs3785793 was associated with decreased protein expression and increased recurrence outcome in pediatric ES. These findings suggest XAF1 polymorphism might be a potential biomarker for outcomes in ES, warranting further validation in larger prospective cohorts.