Study of the Female Sex Survival Advantage in Melanoma-A Focus on X-Linked Epigenetic Regulators and Immune Responses in Two Cohorts

Background: Survival from melanoma is strongly related to patient sex, with females having a survival rate almost twice that of males. Many explanations have been proposed but have not withstood critical scrutiny. Prior analysis of different cancers with a sex bias has identified six X-linked genes that escape X chromosome inactivation in females and are, therefore, potentially involved in sex differences in survival. Four of the genes are well-known epigenetic regulators that are known to influence the expression of hundreds of other genes and signaling pathways in cancer. Methods: Survival and interaction analysis were performed on the skin cutaneous melanoma (SKCM) cohort in The Cancer Genome Atlas (TCGA), comparing high vs. low expression ofKDM6A,ATRX,KDM5C,andDDX3X. The Leeds melanoma cohort (LMC) on 678 patients with primary melanoma was used as a validation cohort. Results: Analysis of TCGA data revealed that two of these genes-KDM6AandATRX-were associated with improved survival from melanoma. TumoralKDM6Awas expressed at higher levels in females and was associated with inferred lymphoid infiltration into melanoma. Gene set analysis of highKDM6Ashowed strong associations with immune responses and downregulation of genes associated with Myc and other oncogenic pathways. The LMC analysis confirmed the prognostic significance ofKDM6Aand its interaction withEZH2but also revealed the expression ofKDM5CandDDX3Xto be prognostically significant. The analysis also confirmed a partial correlation ofKDM6Awith immune tumor infiltrates. Conclusion: When considered together, the results from these two series are consistent with the involvement of X-linked epigenetic regulators in the improved survival of females from melanoma. The identification of gene signatures associated with their expression presents insights into the development of new treatment initiatives but provides a basis for exploration in future studies.