X-linked Tumor Suppressor Escape and Sex Dimorphism in Cancer: Implications for Risk Stratification and Prevention

Epidemiological data demonstrate a marked male bias in incidence and mortality across most non-reproductive cancers.Beyond behavioral and hormonal factors, recent genomic insights highlight the critical role of X-chromosome genetics and epigenetics.Specifically, genes that escape X-chromosome inactivation (XCI)-termed Escape from X-Inactivation Tumor Suppressors (EX-ITS)-provide a female-specific "dosage protection" mechanism against oncogenesis.This review analyzes seven X-linked tumor suppressor genes associated with sex-biased cancer phenotypes (KDM6A, KDM5C, DDX3X, ATRX, PHF6, MAGEC3, and CNKSR2) and their roles in cancer etiology and tumor suppression.Under the two-hit hypothesis, female cells-with two X chromosomes-can offset a loss-of-function mutation on the active X chromosome through normal allele expression from the inactive X chromosome (Xi), lowering susceptibility.Conversely, males with only one X chromosome face a "single-hit vulnerability," in which a single loss-of-function mutation disrupts the tumor-suppressor network.We further note persistent knowledge gaps regarding the remaining X-linked tumor suppressors annotated in the TSGene 2.0 database, reflecting the facultative nature of XCI escape, limited statistical power in existing cohorts, and the underuse of single-cell multi-omic approaches.Elucidating XCI escape and X-linked gene dosage imbalances offers a framework for sex-specific precision oncology.For high-risk male populations, identifying EXITS gene mutations warrants more intensive, shorter-interval screening.In female patients, epigenetic modulators that induce X-reactivation of Xi may offer unique therapeutic benefits.Incorporating X-linked gene dosage parameters into clinical trials and drug development will be essential to overcome sex disparities in cancer prevention and therapy.