Enhanced tumor heterogeneity mediates poor prognosis in females with TP53 mutation in lung adenocarcinoma

TP53 mutation is generally associated with poor prognosis, but its impact may differ by sex. This study aimed to investigate the sex-specific effects of TP53 mutation on prognosis in lung adenocarcinoma patients. Univariate and multivariate Cox regression analyses were performed to assess the prognostic significance of TP53 between sexes, and multi-omics data were used to explore underlying sex-related mechanisms. The results demonstrated that TP53 mutation predicted worse overall survival in females (TCGA: HR = 2.07, P = 0.004; CPTAC: HR = 3.05, P = 0.045; Our Internal Cohort: HR = 5.40, P = 0.011; MSK: P = 0.014), but not in males. Females with TP53 mutation showed higher tumor heterogeneity compared to the wild-type (TCGA: P = 0.018; CPTAC: P = 0.012), while the difference not observed in males. Furthermore, multi-omics analysis identified prognostic subtypes in males (TCGA: HR = 3.05, P = 0.039; CPTAC: HR = 2.84, P = 0.006). The poor-outcome subtype had higher heterogeneity (TCGA: P = 0.003, CPTAC: P = 0.430). These findings indicate that TP53 mutation is linked to poorer survival in female lung adenocarcinoma patients, potentially due to elevated tumor heterogeneity.