Int J Cancer. 2024 Dec 20. doi: 10.1002/ijc.35310. Online ahead of print.
ABSTRACT
This study evaluates the H2AX/γ-H2AX expression in soft tissue sarcomas (STS), its implications for biological behavior and immune environment, and its potential as a prognostic biomarker. RNA-Seq data from 237 STS were obtained from The Cancer Genome Atlas project. Patients were stratified by H2AX mRNA expression using a survival-associated cutoff. Differentially expressed genes and pathways as well as immune signatures between H2AXhigh– and H2AXlow tumors were identified with DESeq2 analysis, gene set enrichment analyses (GSEA), Enrichr pathway analysis and CIBERSORTx. Tissue microarrays of a different cohort of 291 STS were generated for immunohistochemical staining to assess γ-H2AX protein expression, followed by statistical evaluation. High H2AX mRNA expression was associated with shorter overall survival (OS) in STS (p = 0.02), particularly in leiomyosarcomas (LMS) (p < 0.001), and was a negative prognostic factor in LMS (HR 11.15, p < 0.001). H2AXhigh LMS tumors showed upregulation of cell cycle-related pathways, while H2AXlow LMS exhibited increased inflammatory activity, including elevated M1 macrophage signatures and resting mast cell signatures (both p < 0.001). High γ-H2AX protein levels were an independent negative prognostic factor in the total LMS cohort (HR 12.12, p = 0.025) and in the subgroup of non-uterine LMS (HR 153.80, p = 0.013). Consistent with CIBERSORTx analysis, γ-H2AXlow LMS showed higher mast cell infiltration than γ-H2AXhigh LMS (p = 0.038). In conclusion, H2AX mRNA and γ-H2AX protein expression are associated with distinct biological behavior, differences in the immune cell environment, and might serve as useful prognostic biomarkers in LMS.
PMID:39707602 | DOI:10.1002/ijc.35310
