Role of DNA Methylation and Epigenetic Silencing of HAND2 in Endometrial Cancer Development
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{"title"=>"Role of DNA Methylation and Epigenetic Silencing of HAND2 in Endometrial Cancer Development", "type"=>"journal", "authors"=>[{"first_name"=>"Allison", "last_name"=>"Jones", "scopus_author_id"=>"7407102219"}, {"first_name"=>"Andrew E.", "last_name"=>"Teschendorff", "scopus_author_id"=>"8528968400"}, {"first_name"=>"Quanxi", "last_name"=>"Li", "scopus_author_id"=>"55540699800"}, {"first_name"=>"Jane D.", "last_name"=>"Hayward", "scopus_author_id"=>"55880761900"}, {"first_name"=>"Athilakshmi", "last_name"=>"Kannan", "scopus_author_id"=>"8211865000"}, {"first_name"=>"Tim", "last_name"=>"Mould", "scopus_author_id"=>"6601965754"}, {"first_name"=>"James", "last_name"=>"West", "scopus_author_id"=>"57198902459"}, {"first_name"=>"Michal", "last_name"=>"Zikan", "scopus_author_id"=>"6507167275"}, {"first_name"=>"David", "last_name"=>"Cibula", "scopus_author_id"=>"7006225985"}, {"first_name"=>"Heidi", "last_name"=>"Fiegl", "scopus_author_id"=>"6602633455"}, {"first_name"=>"Shih Han", "last_name"=>"Lee", "scopus_author_id"=>"55156775300"}, {"first_name"=>"Elisabeth", "last_name"=>"Wik", "scopus_author_id"=>"6504414665"}, {"first_name"=>"Richard", "last_name"=>"Hadwin", "scopus_author_id"=>"24066741100"}, {"first_name"=>"Rupali", "last_name"=>"Arora", "scopus_author_id"=>"35071017200"}, {"first_name"=>"Charlotte", "last_name"=>"Lemech", "scopus_author_id"=>"37091105800"}, {"first_name"=>"Henna", "last_name"=>"Turunen", "scopus_author_id"=>"55912895500"}, {"first_name"=>"Päivi", "last_name"=>"Pakarinen", "scopus_author_id"=>"35563278800"}, {"first_name"=>"Ian J.", "last_name"=>"Jacobs", "scopus_author_id"=>"34975076100"}, {"first_name"=>"Helga B.", "last_name"=>"Salvesen", "scopus_author_id"=>"7004474802"}, {"first_name"=>"Milan K.", "last_name"=>"Bagchi", "scopus_author_id"=>"7004828233"}, {"first_name"=>"Indrani C.", "last_name"=>"Bagchi", "scopus_author_id"=>"7003992474"}, {"first_name"=>"Martin", "last_name"=>"Widschwendter", "scopus_author_id"=>"7006520678"}], "year"=>2013, "source"=>"PLoS Medicine", "identifiers"=>{"pui"=>"370401977", "sgr"=>"84889021277", "issn"=>"15491277", "pmid"=>"24265601", "scopus"=>"2-s2.0-84889021277", "doi"=>"10.1371/journal.pmed.1001551", "isbn"=>"1549-1676"}, "id"=>"2026cf6c-91ba-37e5-9abd-3accaa6665d8", "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.\\n\\nMETHODS 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.\\n\\nCONCLUSIONS: 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.", "link"=>"http://www.mendeley.com/research/role-dna-methylation-epigenetic-silencing-hand2-endometrial-cancer-development-1", "reader_count"=>60, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>5, "Researcher"=>9, "Student > Doctoral Student"=>1, "Student > Ph. D. 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  • {"files"=>["https://ndownloader.figshare.com/files/1277389", "https://ndownloader.figshare.com/files/1277390", "https://ndownloader.figshare.com/files/1277391", "https://ndownloader.figshare.com/files/1277392", "https://ndownloader.figshare.com/files/1277393", "https://ndownloader.figshare.com/files/1277394", "https://ndownloader.figshare.com/files/1277395", "https://ndownloader.figshare.com/files/1277396", "https://ndownloader.figshare.com/files/1277397", "https://ndownloader.figshare.com/files/1277398", "https://ndownloader.figshare.com/files/1277399", "https://ndownloader.figshare.com/files/1277400", "https://ndownloader.figshare.com/files/1277401", "https://ndownloader.figshare.com/files/1277402", "https://ndownloader.figshare.com/files/1277403", "https://ndownloader.figshare.com/files/1277404", "https://ndownloader.figshare.com/files/1277405", "https://ndownloader.figshare.com/files/1277406", "https://ndownloader.figshare.com/files/1277407", "https://ndownloader.figshare.com/files/1277408", "https://ndownloader.figshare.com/files/1277409", "https://ndownloader.figshare.com/files/1277410", "https://ndownloader.figshare.com/files/1277411", "https://ndownloader.figshare.com/files/1277412", "https://ndownloader.figshare.com/files/1277413", "https://ndownloader.figshare.com/files/1277414"], "description"=>"<div><p>Background</p><p>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.</p><p>Methods and Findings</p><p>Epigenome-wide methylation analysis of >27,000 CpG sites in endometrial cancer tissue samples (<i>n</i> = 64) and control samples (<i>n</i> = 23) revealed that <i>HAND2</i> (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 <i>HAND2</i> 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 <i>HAND2</i> 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 <i>HAND2</i> methylation in their premalignant lesions were less likely to respond to progesterone treatment. <i>HAND2</i> 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 <i>Hand2</i> 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.</p><p>Conclusions</p><p><i>HAND2</i> 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 <i>HAND2</i> DNA methylation, however, requires further validation in prospective studies.</p><p><i>Please see later in the article for the Editors' Summary</i></p></div>", "links"=>[], "tags"=>["dna", "methylation", "epigenetic", "endometrial", "cancer"], "article_id"=>847975, "categories"=>["Biological Sciences"], "users"=>["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", "Päivi Pakarinen", "Ian J. Jacobs", "Helga B. Salvesen", "Milan K. Bagchi", "Indrani C. Bagchi", "Martin Widschwendter"], "doi"=>["https://dx.doi.org/10.1371/journal.pmed.1001551.s001", "https://dx.doi.org/10.1371/journal.pmed.1001551.s002", "https://dx.doi.org/10.1371/journal.pmed.1001551.s003", "https://dx.doi.org/10.1371/journal.pmed.1001551.s004", "https://dx.doi.org/10.1371/journal.pmed.1001551.s005", "https://dx.doi.org/10.1371/journal.pmed.1001551.s006", "https://dx.doi.org/10.1371/journal.pmed.1001551.s007", "https://dx.doi.org/10.1371/journal.pmed.1001551.s008", "https://dx.doi.org/10.1371/journal.pmed.1001551.s009", "https://dx.doi.org/10.1371/journal.pmed.1001551.s010", "https://dx.doi.org/10.1371/journal.pmed.1001551.s011", "https://dx.doi.org/10.1371/journal.pmed.1001551.s012", "https://dx.doi.org/10.1371/journal.pmed.1001551.s013", "https://dx.doi.org/10.1371/journal.pmed.1001551.s014", "https://dx.doi.org/10.1371/journal.pmed.1001551.s015", "https://dx.doi.org/10.1371/journal.pmed.1001551.s016", "https://dx.doi.org/10.1371/journal.pmed.1001551.s017", "https://dx.doi.org/10.1371/journal.pmed.1001551.s018", "https://dx.doi.org/10.1371/journal.pmed.1001551.s019", "https://dx.doi.org/10.1371/journal.pmed.1001551.s020", "https://dx.doi.org/10.1371/journal.pmed.1001551.s021", "https://dx.doi.org/10.1371/journal.pmed.1001551.s022", "https://dx.doi.org/10.1371/journal.pmed.1001551.s023", "https://dx.doi.org/10.1371/journal.pmed.1001551.s024", "https://dx.doi.org/10.1371/journal.pmed.1001551.s025", "https://dx.doi.org/10.1371/journal.pmed.1001551.s026"], "stats"=>{"downloads"=>104, "page_views"=>29, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Role_of_DNA_Methylation_and_Epigenetic_Silencing_of_HAND2_in_Endometrial_Cancer_Development/847975", "title"=>"Role of DNA Methylation and Epigenetic Silencing of <i>HAND2</i> in Endometrial Cancer Development", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-11-12 03:34:24"}
  • {"files"=>["https://ndownloader.figshare.com/files/1277364"], "description"=>"<p>(A) Scatter plot of the MethyLight PMR profile and the gene expression profile of sample Set 3 showing 24 normal endometrium samples (in green) and 101 endometrial cancer samples (in red). The correlation between the two profiles was tested by the Spearman's rank correlation test with the correlation coefficient ρ and corresponding <i>p</i>-value (P). (B) Analysis of 34 molecular factors and association with <i>HAND2</i> methylation (Set1; <a href=\"http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001551#pmed.1001551.s024\" target=\"_blank\">Table S12</a>). The nine molecular cancer subgroups with significant heterogeneity between samples are displayed, and the <i>p</i>-values for the Wilcoxon rank sum test (WT) and <i>t</i>-test (TT) are provided separately. Boxes are median (interquartile range), and whiskers indicate range. (C) ROC curves measuring the sensitivity and specificity of <i>HAND2</i> methylation in vaginal swabs to discriminate women with stage 1A endometrial cancer (<i>n</i> = 18) from women with non-cancerous causes (<i>n</i> = 17) for postmenopausal bleeding (Set 4). PMR values as continuous variables were used for the analysis. AUC and <i>p</i>-values (P) as specified. IHC, immunohistochemistry; mut, mutation.</p>", "links"=>[], "tags"=>["methylation", "molecular", "invasive", "endometrial"], "article_id"=>847953, "categories"=>["Biological Sciences"], "users"=>["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", "Päivi Pakarinen", "Ian J. Jacobs", "Helga B. Salvesen", "Milan K. Bagchi", "Indrani C. Bagchi", "Martin Widschwendter"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001551.g002", "stats"=>{"downloads"=>1, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Association_of_HAND2_methylation_with_molecular_and_clinical_features_in_invasive_endometrial_cancer_/847953", "title"=>"Association of <i>HAND2</i> methylation with molecular and clinical features in invasive endometrial cancer.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-11-12 03:34:24"}
  • {"files"=>["https://ndownloader.figshare.com/files/1277362"], "description"=>"<p>(A) Volcano plot of epigenome-wide differential DNAme analysis for all 27,578 probes. The <i>x</i>-axis indicates the median β-value difference between the normal and cancerous endometrial samples (median[cancer] – median[normal]), while the <i>y</i>-axis indicates the −log<sub>e</sub> scale of <i>q</i>-values obtained from a supervised logistic regression analysis testing the association of methylation with normal/cancer status (Set 1). Stem cell PCGT CpGs are highlighted in green, the two <i>HAND2</i> CpGs in red. 353 PCGT CpGs are hypermethylated, and 19 PCGT CpGs are hypomethylated, with enrichment odds ratio (OR) and <i>p</i>-value (P) obtained from a one-sided Fisher's exact test. The horizontal dotted lines mark the significance cutoffs. (B) Integrative DNA methylome (DNAm)–interactome analysis to identify differential methylation hotspots in the network. Briefly, edge weights in the interactome network reflect the combined differential methylation statistics (absolute values) of the genes making up the edge (the CpG closest to the transcription start site [TSS] of the gene was chosen). A spin-glass module detection algorithm was subsequently used to identify subnetworks where the average edge weight (“modularity”) is higher than random, as assessed by randomly rewiring the network preserving node degrees. Statistical significance of the subnetworks was further assessed by comparing their modularities to those obtained by permuting differential methylation statistics over the network. Subnetworks with <i>p</i><0.05 were called EpiMods. (C) Bar plot of modularity values of the top 19 EpiMods with seed genes as indicated. Asterisks mark those hotspots that remain significant in an integrated DNAme and gene expression interactome analysis, i.e., FEM analysis. (D) The <i>HAND2</i> EpiMod. (E) The location of Illumina Infinium HumanMethylation27K array <i>HAND2</i> probes and MethyLight reactions (incorporating [inc.] the Illumina HAND2 CpGs) and the sequenced region (grey bar) of <i>HAND2</i>. hyperM, hypermethylation; hypoM, hypomethylation.</p>", "links"=>[], "tags"=>["methylation", "endometrial"], "article_id"=>847951, "categories"=>["Biological Sciences"], "users"=>["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", "Päivi Pakarinen", "Ian J. Jacobs", "Helga B. Salvesen", "Milan K. Bagchi", "Indrani C. Bagchi", "Martin Widschwendter"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001551.g001", "stats"=>{"downloads"=>3, "page_views"=>23, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Discovery_of_HAND2_methylation_as_a_core_feature_in_endometrial_cancer_/847951", "title"=>"Discovery of <i>HAND2</i> methylation as a core feature in endometrial cancer.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-11-12 03:34:24"}
  • {"files"=>["https://ndownloader.figshare.com/files/1277376"], "description"=>"<p>(A and B) Hematoxylin and eosin staining of uterine sections from <i>Hand2<sup>f/f</sup></i> (A) and <i>Hand2<sup>d/d</sup></i> (B) mice (<i>n</i> = 5). Representative uterine sections obtained from mice at 24–48 wk of age are shown. Closely packed, irregular-shaped glands and features consistent with CAH are evident in uteri lacking <i>Hand2</i>. Note multiple layers of glandular epithelium in <i>Hand2<sup>d/d</sup></i> uteri. Magnification 40×. (C–F) Phospho-FRS2 immunofluorescence in sections from <i>Hand2<sup>f/f</sup></i> (C) (boxed region in [C] further magnified in [D]) and <i>Hand2<sup>d/d</sup></i> (E) (boxed region in [E] further magnified in [F]) mice (<i>n</i> = 3). Magnification 20× (C and E) and 40× (D and F). (G–J) PTEN immunofluorescence in sections from <i>Hand2<sup>f/f</sup></i> (G) (boxed region in [G] further magnified in [H]) and <i>Hand2<sup>d/d</sup></i> (I) (boxed region in [I] further magnified in [J]) mice. Magnification 20× (G and I) and 40× (H and J) (<i>n</i> = 3).</p>", "links"=>[], "tags"=>["pre-invasive", "neoplastic", "conditional", "knock-out"], "article_id"=>847965, "categories"=>["Biological Sciences"], "users"=>["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", "Päivi Pakarinen", "Ian J. Jacobs", "Helga B. Salvesen", "Milan K. Bagchi", "Indrani C. Bagchi", "Martin Widschwendter"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001551.g005", "stats"=>{"downloads"=>0, "page_views"=>21, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Endometrial_pre_invasive_neoplastic_changes_in_Hand2_conditional_knock_out_mice_/847965", "title"=>"Endometrial pre-invasive neoplastic changes in <i>Hand2</i> conditional knock-out mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-11-12 03:34:24"}
  • {"files"=>["https://ndownloader.figshare.com/files/1277369"], "description"=>"<p>(A–F) Sections of uteri obtained from <i>Hand2<sup>f/f</sup></i> (control) and <i>Hand2<sup>d/d</sup></i> (null) mice were subjected to immunohistochemical staining with an antibody to cytokeratin 8, which marks the epithelial cells. Uterine sections were collected from mice of both genotypes at different ages. Representative uterine sections obtained from mice (<i>n</i> = 12) at 8–10 (A and D), 24–32 (B and E), and 40–48 (C and F) wk of age are shown. Note the increase in the gland/stroma ratio and the irregularity in the shape and size of the glands in <i>Hand2<sup>d/d</sup></i> uteri compared to <i>Hand2<sup>f/f</sup></i> uteri. G, gland; S, stroma. Magnification 20×. (G) Boxplots comparing the number of glands in uterine sections of <i>Hand2<sup>f/f</sup></i> (control) and <i>Hand2<sup>d/d</sup></i> (null) mice as a function of age. The number of endometrial glands was determined by counting the glands from three different regions of the uterine horn and is expressed as mean ± standard error. Statistical analysis was performed using a <i>t</i>-test. Boxes are median (interquartile range), and whiskers indicate range.</p>", "links"=>[], "tags"=>["hyperplasia", "conditional", "knock-out", "mice"], "article_id"=>847958, "categories"=>["Biological Sciences"], "users"=>["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", "Päivi Pakarinen", "Ian J. Jacobs", "Helga B. Salvesen", "Milan K. Bagchi", "Indrani C. Bagchi", "Martin Widschwendter"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001551.g004", "stats"=>{"downloads"=>3, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Endometrial_hyperplasia_in_Hand2_conditional_knock_out_mice_as_a_function_of_age_/847958", "title"=>"Endometrial hyperplasia in <i>Hand2</i> conditional knock-out mice as a function of age.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-11-12 03:34:24"}
  • {"files"=>["https://ndownloader.figshare.com/files/1277366"], "description"=>"<p>(A) Boxplot comparing the differences in the <i>HAND2</i> MethyLight PMR profiles in endometrial samples from women without any endometrial pathology (N [Normal], <i>n</i> = 10), in normal endometrium from women with CAH (N [CAH], <i>n</i> = 7), in CAH samples (CAH, <i>n</i> = 8), and in endometrioid endometrial cancer samples (Endo CA, <i>n</i> = 12). (B) Boxplots (top panel) comparing DNAme (MethyLight) and HAND2 protein expression (immunohistochemistry quantified by means of the Allred Score) in three different endometrial conditions with increasing potential for malignant transformation (simple hyperplasia [SH], <i>n</i> = 17; complex hyperplasia [CH], <i>n</i> = 10; CAH, <i>n</i> = 7). The lower panel gives an example of the corresponding HAND2 nuclear protein expression in stromal cells in simple hyperplasia compared to loss of stromal expression in CAH. (C) Boxplot comparing the differences in the <i>HAND2</i> MethyLight PMR profiles in endometrial cancer from patients treated with progesterone according to whether they had clinically responded (<i>n</i> = 29) or were non-responsive (<i>n</i> = 13) to treatment. All <i>p</i>-values were obtained from the two-sided Wilcoxon rank sum test. Boxes are median (interquartile range), and whiskers indicate range.</p>", "links"=>[], "tags"=>["methylation", "endometrial"], "article_id"=>847955, "categories"=>["Biological Sciences"], "users"=>["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", "Päivi Pakarinen", "Ian J. Jacobs", "Helga B. Salvesen", "Milan K. Bagchi", "Indrani C. Bagchi", "Martin Widschwendter"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001551.g003", "stats"=>{"downloads"=>2, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_HAND2_methylation_in_human_endometrial_carcinogenesis_/847955", "title"=>"<i>HAND2</i> methylation in human endometrial carcinogenesis.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-11-12 03:34:24"}

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Relative Metric

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