Sex-based molecular and prognostic disparities in pan-cancer: an analysis across the global cohorts

Biological sex influences cancer risk, molecular profiles, and clinical outcomes, yet its role in non-reproductive cancers remains underexplored.

This study investigated sex-based differences in somatic mutations, copy number alterations (CNAs), and overall survival (OS) across 34,782 patients from three global pan-cancer cohorts (TCGA, MSK MetTropism, and China OrigiMed), excluding reproductive cancers to minimize confounders. Sex-specific genetic alterations were assessed using Fisher's exact test, while OS differences were evaluated with Kaplan-Meier and Cox proportional hazards models.

Incidence patterns revealed a strong male predominance in esophageal, liver, bladder, and head and neck cancers, whereas thyroid and gallbladder cancers were more common in females. OS analysis showed a consistent female advantage in both primary and metastatic cohorts, with males experiencing poorer OS in lung adenocarcinoma, glioblastoma, and pancreatic adenocarcinoma, although colorectal cancer with hepatic metastases favored males. Mutational profiling revealed that the TP53, CDKN2A, and TTN mutations were more frequent in males, while EGFR, KRAS, BRAF, and PIK3CA mutations occurred more often in females. Notably, BRAF and EGFR mutations were associated with better survival in females. CNAs analysis demonstrated male-biased amplifications, including CCND1 and the FGF cluster in the China cohort, and MYC, CCND1, and ERBB2 in the TCGA and MSK cohorts. In contrast, MDM2 amplification was enriched in females in the China cohort.

These findings highlight both shared and population-specific molecular differences and underscore the importance of integrating sex as a biological variable in cancer genomics, biomarker development, and clinical trial design.