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PLoS Med.:HAND2基因的表观修饰促进子宫内膜瘤发育

  1. 子宫内膜瘤

来源:生物谷 2013-11-13 13:09

一项本周发表在PLOS Medicine上的文章称HAND2基于的表观修饰在子宫内膜瘤发育中起重要作用

2013年11月13日讯 /生物谷BIOON/--一项本周发表在PLOS Medicine上的文章称HAND2基于的表观修饰在子宫内膜瘤发育中起重要作用。HAND2在健康子宫内膜中处于激活状态,用于对抗雌激素的诱导生长作用。但是在多于90%的子宫内膜瘤中该基因处于过度甲基化状态,而甲基化会抑制基因表达。

Martin Widschwendter博士领导的研究团队系统的比较了子宫内膜瘤细胞和正常子宫内膜细胞的基因甲基化情况。采用生物信息学方法,科学家鉴定出HAND2基因是子宫内膜瘤细胞的甲基化热点。

科学家发现HAND2甲基化在子宫内膜癌变前就已经增加了,而高水平的HAND2甲基化与治疗预后差相关。

该文章的通讯作者Widschwendter博士称,我们的工作表明不仅遗传突变会导致癌症产生,表观遗传学变化也会引起癌症。(生物谷Bioon.com)

Role of DNA Methylation and Epigenetic Silencing of HAND2 in Endometrial Cancer Development

Allison Jones, Andrew E. Teschendorff, Quanxi Li, Jane D. Hayward, Athilakshmi Kannan, Tim Mould, James West, Michal Zikan, David Cibula, Heidi Fiegl, Shih-Han Lee, Elisabeth Wik, Richard Hadwin, Rupali Arora, Charlotte Lemech, Henna Turunen, P?ivi Pakarinen, Ian J. Jacobs, Helga B. Salvesen, Milan K. Bagchi, Indrani C. Bagchi, Martin Widschwendter

Background Endometrial cancer incidence is continuing to rise in the wake of the current ageing and obesity epidemics. Much of the risk for endometrial cancer development is influenced by the environment and lifestyle. Accumulating evidence suggests that the epigenome serves as the interface between the genome and the environment and that hypermethylation of stem cell polycomb group target genes is an epigenetic hallmark of cancer. The objective of this study was to determine the functional role of epigenetic factors in endometrial cancer development. Methods and Findings Epigenome-wide methylation analysis of >27,000 CpG sites in endometrial cancer tissue samples (n = 64) and control samples (n = 23) revealed that HAND2 (a gene encoding a transcription factor expressed in the endometrial stroma) is one of the most commonly hypermethylated and silenced genes in endometrial cancer. A novel integrative epigenome-transcriptome-interactome analysis further revealed that HAND2 is the hub of the most highly ranked differential methylation hotspot in endometrial cancer. These findings were validated using candidate gene methylation analysis in multiple clinical sample sets of tissue samples from a total of 272 additional women. Increased HAND2 methylation was a feature of premalignant endometrial lesions and was seen to parallel a decrease in RNA and protein levels. Furthermore, women with high endometrial HAND2 methylation in their premalignant lesions were less likely to respond to progesterone treatment. HAND2 methylation analysis of endometrial secretions collected using high vaginal swabs taken from women with postmenopausal bleeding specifically identified those patients with early stage endometrial cancer with both high sensitivity and high specificity (receiver operating characteristics area under the curve = 0.91 for stage 1A and 0.97 for higher than stage 1A). Finally, mice harbouring a Hand2 knock-out specifically in their endometrium were shown to develop precancerous endometrial lesions with increasing age, and these lesions also demonstrated a lack of PTEN expression. Conclusions HAND2 methylation is a common and crucial molecular alteration in endometrial cancer that could potentially be employed as a biomarker for early detection of endometrial cancer and as a predictor of treatment response. The true clinical utility of HAND2 DNA methylation, however, requires further validation in prospective studies.

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