title: Role of DNA methylation and epigenetic silencing of HAND2 in endometrial cancer development.
abstract: 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.
  
  
  RESULTS
  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. Please see later in the article for the Editors' Summary.
authors.affiliation: Department of Women's Cancer, UCL Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, United Kingdom.
authors.forename: Allison
authors.initials: A
authors.lastname: Jones
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Teschendorff
authors.forename: Quanxi
authors.initials: Q
authors.lastname: Li
authors.forename: Jane D
authors.initials: JD
authors.lastname: Hayward
authors.forename: Athilakshmi
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authors.lastname: Kannan
authors.forename: Tim
authors.initials: T
authors.lastname: Mould
authors.forename: James
authors.initials: J
authors.lastname: West
authors.forename: Michal
authors.initials: M
authors.lastname: Zikan
authors.forename: David
authors.initials: D
authors.lastname: Cibula
authors.forename: Heidi
authors.initials: H
authors.lastname: Fiegl
authors.forename: Shih-Han
authors.initials: SH
authors.lastname: Lee
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Wik
authors.forename: Richard
authors.initials: R
authors.lastname: Hadwin
authors.forename: Rupali
authors.initials: R
authors.lastname: Arora
authors.forename: Charlotte
authors.initials: C
authors.lastname: Lemech
authors.forename: Henna
authors.initials: H
authors.lastname: Turunen
authors.forename: Päivi
authors.initials: P
authors.lastname: Pakarinen
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Jacobs
authors.forename: Helga B
authors.initials: HB
authors.lastname: Salvesen
authors.forename: Milan K
authors.initials: MK
authors.lastname: Bagchi
authors.forename: Indrani C
authors.initials: IC
authors.lastname: Bagchi
authors.forename: Martin
authors.initials: M
authors.lastname: Widschwendter
mesh_terms: D000368:Aged; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D042241:Early Diagnosis; D016889:Endometrial Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004717:Endometrium / Q000473:pathology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D011374:Progesterone / Q000627:therapeutic use; D012313:RNA / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051059:PTEN Phosphohydrolase; D011374:Progesterone; D012313:RNA; C498765:HAND2 protein, human; C498766:Hand2 protein, mouse; C487757:Pten protein, mouse