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Article

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

by
Abdullah Al Emran
1,2,
Jérémie Nsengimana
3,4,
Gaya Punnia-Moorthy
1,2,
Ulf Schmitz
5,6,7,
Stuart J. Gallagher
1,2,
Julia Newton-Bishop
3,†,
Jessamy C. Tiffen
1,2,† and
Peter Hersey
1,2,*,†
1
Melanoma Oncology and Immunology Program, The Centenary Institute, The University of Sydney, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW 2050, Australia
2
Melanoma Institute Australia, The University of Sydney, Sydney NSW 2006, Australia
3
Leeds Institute of Medical Research at St James’s, University of Leeds, Leeds LS2 9JT, UK
4
Biostatistics Research Group, Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
5
Computational Biomedicine Lab Centenary Institute, The University of Sydney, Camperdown NSW 2050, Australia
6
Gene & Stem Cell Therapy Program Centenary Institute, The University of Sydney, Camperdown NSW 2050, Australia
7
Faculty of Medicine and Health, The University of Sydney, Camperdown NSW 2050, Australia
*
Author to whom correspondence should be addressed.
†
Equal contribution.
Cancers 2020, 12(8), 2082; https://doi.org/10.3390/cancers12082082
Received: 26 June 2020 / Revised: 15 July 2020 / Accepted: 23 July 2020 / Published: 28 July 2020
(This article belongs to the Section Cancer Biomarkers)
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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. View Full-Text
Keywords: melanoma; sex difference; X-linked genes; X chromosome inactivation; epigenetic regulators; histone demethylase; EZH2 inhibitor; GSEA; immune response; survival; TCGA; SKCM; LMC melanoma; sex difference; X-linked genes; X chromosome inactivation; epigenetic regulators; histone demethylase; EZH2 inhibitor; GSEA; immune response; survival; TCGA; SKCM; LMC
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MDPI and ACS Style

Emran, A.A.; Nsengimana, J.; Punnia-Moorthy, G.; Schmitz, U.; Gallagher, S.J.; Newton-Bishop, J.; Tiffen, J.C.; Hersey, P. Study of the Female Sex Survival Advantage in Melanoma—A Focus on X-Linked Epigenetic Regulators and Immune Responses in Two Cohorts. Cancers 2020, 12, 2082. https://doi.org/10.3390/cancers12082082

AMA Style

Emran AA, Nsengimana J, Punnia-Moorthy G, Schmitz U, Gallagher SJ, Newton-Bishop J, Tiffen JC, Hersey P. Study of the Female Sex Survival Advantage in Melanoma—A Focus on X-Linked Epigenetic Regulators and Immune Responses in Two Cohorts. Cancers. 2020; 12(8):2082. https://doi.org/10.3390/cancers12082082

Chicago/Turabian Style

Emran, Abdullah A., Jérémie Nsengimana, Gaya Punnia-Moorthy, Ulf Schmitz, Stuart J. Gallagher, Julia Newton-Bishop, Jessamy C. Tiffen, and Peter Hersey. 2020. "Study of the Female Sex Survival Advantage in Melanoma—A Focus on X-Linked Epigenetic Regulators and Immune Responses in Two Cohorts" Cancers 12, no. 8: 2082. https://doi.org/10.3390/cancers12082082

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