Evaluation of the association between sex-linked genes and treatment response in lung cancer.

Abstract

The impact of biological sex on treatment response and prognosis in lung cancer remains poorly understood. This study investigates the relationship between sex-linked genes, DNA repair, senescence, and survival in male and female patients with lung cancer. Whole-genome mRNA expression data from The Cancer Genome Atlas (TCGA) PanCancer Atlas for lung adenocarcinoma (LUAD) were analyzed (N = 275 female, N = 239 male). Curated lists of 874 X-linked, 57 Y-linked, and 314 DNA damage response (DDR) genes were obtained from UniProt and HUGO. Additionally, 279 senescence genes were sourced from Senescence.info. Overall survival (OS) was assessed using Kaplan-Meier analysis. Correlation analyses between sex-linked and DDR/senescence genes used Spearman's rank correlation. Based on their strong association with DDR genes and OS in patient tumours, two top-ranked X-linked genes, CENPI and ERCC6L, were further evaluated in vitro in male (A549) and female (H1975) lung adenocarcinoma cells after radiation or fisetin treatment. Of 44 Y-linked genes evaluated, 11 were differentially expressed; PRKY was significantly associated with OS. In tumours, 287 (male) and 314 (female) X-linked genes were altered, with strong correlations to DDR genes. Low ERCC6L expression was linked to increased OS in males treated with radiation (p = 0.036, HR = 3.1). Radiation and fisetin treatment modified CENPI and ERCC6L expression in a sex-specific manner. Sex-linked gene expression in lung tumours influences DDR and senescence pathways, correlating with survival outcomes. These findings highlight the importance of sex-specific analysis in lung cancer research and treatment.