Abstract

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. 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. 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. Please see later in the article for the Editors' Summary.

Highlights

  • 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

  • Accumulating evidence suggests that the epigenome serves as the interface between the genome and the environment [1,2] and that hypermethylation of stem cell polycomb group target genes (PCGTs—targets for chromatin-modifying complexes that transiently suppress expression and temporarily repress cellular differentiation required for development and stem cell renewal) is an epigenetic hallmark of cancer [3,4]

  • Principal component analysis demonstrated that the top component, accounting for over 90% of the variation in the data, was strongly associated with DNA methylation (DNAme) differences between normal and cancerous endometrium (Wilcoxon rank sum test p,10210; Figure S4)

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Summary

Introduction

Accumulating evidence suggests that the epigenome serves as the interface between the genome and the environment [1,2] and that hypermethylation of stem cell polycomb group target genes (PCGTs—targets for chromatin-modifying complexes that transiently suppress expression and temporarily repress cellular differentiation required for development and stem cell renewal) is an epigenetic hallmark of cancer [3,4]. Several lines of evidence suggest that methylation of PCGTs, as triggered by environmental factors and age [5,8], reduces cellular differentiation, leading to an accumulation of undifferentiated cells susceptible to cancer development [7,9,10]. The methylation of PCGTs, which is triggered by age and by environmental factors that are associated with cancer development, reduces cellular differentiation and leads to the accumulation of undifferentiated cells that are susceptible to cancer development. It is unclear, whether epigenetic modifications have a causal role in carcinogenesis. Endometrial cancer is an ideal model in which to study whether epigenetic mechanisms underlie carcinogenesis

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