Emran Abdullah Al, Nsengimana Jérémie, Punnia-Moorthy Gaya, Schmitz Ulf, Gallagher Stuart J, Newton-Bishop Julia, Tiffen Jessamy C, Hersey Peter
Melanoma Oncology and Immunology Program, The Centenary Institute, The University of Sydney, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW 2050, Australia.
Melanoma Institute Australia, The University of Sydney, Sydney NSW 2006, Australia.
Cancers (Basel). 2020 Jul 28;12(8):2082. doi: 10.3390/cancers12082082.
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.
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 , , and . The Leeds melanoma cohort (LMC) on 678 patients with primary melanoma was used as a validation cohort.
Analysis of TCGA data revealed that two of these genes- and -were associated with improved survival from melanoma. Tumoral was expressed at higher levels in females and was associated with inferred lymphoid infiltration into melanoma. Gene set analysis of high 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 and its interaction with but also revealed the expression of and to be prognostically significant. The analysis also confirmed a partial correlation of with immune tumor infiltrates.
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.
黑色素瘤患者的生存率与患者性别密切相关，女性的生存率几乎是男性的两倍。人们提出了许多解释，但都经不起严格审查。先前对存在性别偏差的不同癌症的分析确定了六个X连锁基因，这些基因在女性中逃避X染色体失活，因此可能与生存的性别差异有关。其中四个基因是众所周知的表观遗传调节因子，已知它们会影响癌症中数百个其他基因的表达和信号通路。
对癌症基因组图谱（TCGA）中的皮肤黑色素瘤（SKCM）队列进行生存和相互作用分析，比较[具体基因1]、[具体基因2]、[具体基因3]和[具体基因4]的高表达与低表达情况。将678例原发性黑色素瘤患者的利兹黑色素瘤队列（LMC）用作验证队列。
对TCGA数据的分析表明，这些基因中的两个——[具体基因1]和[具体基因2]——与黑色素瘤患者生存率的提高相关。肿瘤中的[具体基因1]在女性中表达水平较高，并且与黑色素瘤中推断的淋巴细胞浸润有关。对高表达[具体基因1]的基因集分析显示与免疫反应以及与Myc和其他致癌途径相关基因的下调有很强的关联。LMC分析证实了[具体基因1]的预后意义及其与[具体基因2]的相互作用，但也揭示了[具体基因3]和[具体基因4]的表达具有预后意义。该分析还证实了[具体基因1]与免疫肿瘤浸润存在部分相关性。
综合考虑，这两个系列的结果与X连锁表观遗传调节因子参与女性黑色素瘤患者生存率提高一致。与其表达相关的基因特征的鉴定为新治疗方案的开发提供了见解，但为未来研究的探索提供了基础。
