UC Davis

Abstract: Purpose: Sex influences the incidence, molecular characteristics and clinical outcomes of gliomas, but the biological pathways contributing to these differences are not fully understood. In lower grade glioma (LGG), immune activity and cell cycle dysregulation are key components of tumor behavior. Because sex heavily influences baseline survival, it is critical to determine if the prognostic relevance of these transcriptional programs differs between males and females, or if they offer universal utility. This study evaluated the robustness of immune and cell cycle gene expression signatures as prognostic markers across sex-stratified cohorts in LGG using data from The Cancer Genome Atlas (TCGA). Methods: Clinical and Ribonucleic acid (RNA) sequencing data from 510 patients with lower grade glioma in The Cancer Genome Atlas were analyzed. Only primary tumors with complete information on survival, age, sex, grade and primary diagnosis were included. Raw RNA counts were normalized to log-counts per million using the trimmed mean of M values (TMM) method in edgeR. Two predefined transcriptional signatures were examined: an immune activation signature (CD3D, CD3E, CD8A, CXCL9, CXCL10, GZMB, PDCD1) and a cell cycle proliferation signature (MKI67, PCNA, TOP2A, CCNB1, CDK1, BIRC5). Signature scores were calculated as the mean expression of component genes, standardized to z-scores, and categorized into within-sex tertiles. Associations with overall survival were evaluated using Kaplan–Meier curves and multivariable Cox proportional hazards models. Models adjusted for age and grade included interaction terms to evaluate whether prognostic utility varied by sex. Results: Higher immune and cell cycle signature scores were each associated with shorter overall survival (immune: log-rank p  = 0.0028; cell cycle: p  < 0.0001). In multivariable Cox models adjusted for age and grade, both signatures remained independently associated with mortality (immune HR per SD = 1.58, 95% CI 1.25–2.00; cell-cycle HR = 1.47, 95% CI 1.15–1.89). Crucially, interaction analyses indicated that the prognostic impact of these signatures did not significantly differ between sexes, demonstrating consistent adverse associations across both male and female cohorts. Conclusion: Immune and cell cycle transcriptional programs show robust, independent associations with survival in lower grade glioma that are consistent across sexes. Elevated activity in either pathway is universally linked to poorer outcomes. These findings validate the broad prognostic utility of these transcriptional signatures in LGG, highlighting their potential clinical relevance regardless of patient sex.