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dc.contributor.authorJones, Allisonen_US
dc.contributor.authorTeschendorff, Andrew E.en_US
dc.contributor.authorLi, Quanxien_US
dc.contributor.authorHayward, Jane D.en_US
dc.contributor.authorKannan, Athilakshmien_US
dc.contributor.authorMould, Timen_US
dc.contributor.authorWest, Jamesen_US
dc.contributor.authorZikan, Michalen_US
dc.contributor.authorCibula, Daviden_US
dc.contributor.authorFiegl, Heidien_US
dc.contributor.authorLee, Shih-Hanen_US
dc.contributor.authorWik, Elisabethen_US
dc.contributor.authorHadwin, Richarden_US
dc.contributor.authorArora, Rupalien_US
dc.contributor.authorLemech, Charlotteen_US
dc.contributor.authorTurunen, Hennaen_US
dc.contributor.authorPakarinen, Päivien_US
dc.contributor.authorJacobs, Ian J.en_US
dc.contributor.authorSalvesen, Helga Birgitteen_US
dc.contributor.authorBagchi, Milan K.en_US
dc.contributor.authorBagchi, Indrani C.en_US
dc.contributor.authorWidschwendter, Martinen_US
dc.PublishedPLoS Medicine 2013, 10(11):e1001551eng
dc.description.abstractBackground: 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.en_US
dc.rightsAttribution CC BYeng
dc.titleRole of DNA methylation and epigenetic silencing of HAND2 in endometrial cancer developmenten_US
dc.typePeer reviewed
dc.typeJournal article
dc.rights.holderCopyright 2013 Jones et al.
dc.relation.projectNorges forskningsråd: 223250
dc.relation.projectNorges forskningsråd: 193373
dc.relation.projectNorges forskningsråd: 205404
dc.subject.nsiVDP::Medisinske fag: 700::Klinisk medisinske fag: 750::Gynekologi og obstetrikk: 756
dc.subject.nsiVDP::Midical sciences: 700::Clinical medical sciences: 750::Gynaecology and obstetrics: 756
dc.subject.nsiVDP::Medisinske fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk genetikk: 714
dc.subject.nsiVDP::Midical sciences: 700::Basic medical, dental and veterinary sciences: 710::Medical genetics: 714
dc.subject.nsiVDP::Medisinske fag: 700::Klinisk medisinske fag: 750::Onkologi: 762
dc.subject.nsiVDP::Midical sciences: 700::Clinical medical sciences: 750::Oncology: 762

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