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

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

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.3390/cancers12082082
Journal or Publication Title: Cancers
Volume: 12
Number: 8
Page Range: p. 2082
Date: 2020
Divisions: Melanoma Oncology and Immunology
Depositing User: General Admin
Identification Number: 10.3390/cancers12082082
ISSN: 2072-6694
Date Deposited: 04 Jan 2021 00:09
Abstract:

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 of KDM6A, ATRX, KDM5C, and DDX3X. 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—KDM6A and ATRX—were associated with improved survival from melanoma. Tumoral KDM6A was expressed at higher levels in females and was associated with inferred lymphoid infiltration into melanoma. Gene set analysis of high KDM6A showed strong associations with immune responses and downregulation of genes associated with Myc and other oncogenic pathways. The LMC analysis confirmed the prognostic significance of KDM6A and its interaction with EZH2 but also revealed the expression of KDM5C and DDX3X to be prognostically significant. The analysis also confirmed a partial correlation of KDM6A with 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.

Creators:
Creators
Email
Emran, Abdullah Al
UNSPECIFIED
Nsengimana, Jérémie
UNSPECIFIED
Punnia-Moorthy, Gaya
UNSPECIFIED
Schmitz, Ulf
UNSPECIFIED
Gallagher, Stuart J.
UNSPECIFIED
Newton-Bishop, Julia
UNSPECIFIED
Tiffen, Jessamy C.
UNSPECIFIED
Hersey, Peter
UNSPECIFIED
Last Modified: 04 Jan 2021 00:09
URI: https://eprints.centenary.org.au/id/eprint/817

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