XRCC2 as a prognostic biomarker and immune modulator in sarcoma: a comprehensive multi-omics analysis

XRCC2, a core component of the homologous recombination repair pathway, plays a critical role in maintaining genomic stability. Although XRCC2 has been implicated in multiple cellular processes involved in preserving genome integrity, its biological functions, clinical significance, and immunogenomic associations in sarcoma remain poorly understood. We conducted an integrated multi-omics analysis using transcriptomic, clinical, genomic, and pharmacogenomic data from TCGA, GTEx, and GEO datasets to assess XRCC2 expression, prognostic significance, somatic mutation co-alterations, tumor microenvironment (TME) infiltration, immune activation status, and drug sensitivity. Enrichment analyses were performed to characterize the biological processes associated with XRCC2 dysregulation. Functional validation was conducted by knocking down XRCC2 in two sarcoma cell lines, HOS and 143B. XRCC2 mRNA and protein expression, cell proliferation, colony-forming ability, apoptosis, and tumor growth in xenograft models were subsequently evaluated. Based on the drug sensitivity analysis, CUDC-101 was selected for further in vitro and in vivo experiments to determine its effects on XRCC2 expression and related cellular phenotypes. XRCC2 was significantly overexpressed across multiple cancer types, particularly in sarcomas, compared with normal tissues. High XRCC2 expression was consistently associated with worse overall survival, disease-specific survival, and progression-free survival in multiple sarcoma cohorts, including GSE17679, GSE21050, GSE21257, and GSE59455. Genomic analyses demonstrated that elevated XRCC2 expression was associated with a higher frequency of TP53 mutations, increased tumor mutational burden (TMB), and greater neoantigen load. Immunological profiling further revealed positive associations between XRCC2 expression and immune cell infiltration, immune checkpoint activity, cytolytic activity (CYT), and T cell-inflamed gene expression signatures. Pathway enrichment analyses implicated XRCC2 in cell cycle regulation, DNA repair, and p53 signaling. In vitro, XRCC2 knockdown markedly suppressed sarcoma cell proliferation and colony formation while promoting apoptosis. CUDC-101 treatment reduced XRCC2 expression in a dose-dependent manner and further impaired sarcoma cell viability and survival. Our findings identify XRCC2 as a potential prognostic biomarker and immune modulator in sarcoma, with possible applications in patient stratification and therapeutic decision-making. Functional experiments further support its oncogenic role and highlight XRCC2 as a promising therapeutic target for sarcoma treatment.