Identification and validation of highly frequent CpG island hypermethylation in colorectal adenomas and carcinomas
In our study, whole‐genome methylation arrays were applied to identify novel genes with tumor specific DNA methylation of promoter CpG islands in pre‐malignant and malignant colorectal lesions. Using a combination of Illumina HumanMethylation27 beadchips, Methylation‐Sensitive High Resolution Meltin...
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creator | Øster, Bodil Thorsen, Kasper Lamy, Philippe Wojdacz, Tomasz K. Hansen, Lise Lotte Birkenkamp‐Demtröder, Karin Sørensen, Karina D. Laurberg, Søren Ørntoft, Torben F. Andersen, Claus L. |
description | In our study, whole‐genome methylation arrays were applied to identify novel genes with tumor specific DNA methylation of promoter CpG islands in pre‐malignant and malignant colorectal lesions. Using a combination of Illumina HumanMethylation27 beadchips, Methylation‐Sensitive High Resolution Melting (MS‐HRM) analysis, and Exon arrays (Affymetrix) the DNA methylation pattern of ∼14,000 genes and their transcript levels were investigated in six normal mucosas, six adenomas and 30 MSI and MSS carcinomas. Sixty eight genes with tumor‐specific hypermethylation were identified (p < 0.005). Identified hypermethylated sites were validated in an independent sample set of eight normal mucosas, 12 adenomas, 40 MSS and nine MSI cancer samples. The methylation patterns of 15 selected genes, hypermethylated in adenomas and carcinomas (FLI1, ST6GALNAC5, TWIST1, ADHFE1, JAM2, IRF4, CNRIP1, NRG1 and EYA4), in carcinomas only (ABHD9, AOX1 and RERG), or in MSI but not MSS carcinomas (RAMP2, DSC3 and MLH1) were validated using MS‐HRM. Four of these genes (MLH1, AOX1, EYA4 and TWIST1) had previously been reported to be hypermethylated in CRC. Eleven genes, not previously known to be affected by CRC specific hypermethylation, were identified and validated. Inverse correlation to gene expression was observed for six of the 15 genes with Spearman correlation coefficients ranging from −0.39 to −0.60. For six of these genes the altered methylation patterns had a profound transcriptional association, indicating that methylation of these genes may play a direct regulatory role. The hypermethylation changes often occurred already in adenomas, indicating that they may be used as biomarkers for early detection of CRC. |
doi_str_mv | 10.1002/ijc.25951 |
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Using a combination of Illumina HumanMethylation27 beadchips, Methylation‐Sensitive High Resolution Melting (MS‐HRM) analysis, and Exon arrays (Affymetrix) the DNA methylation pattern of ∼14,000 genes and their transcript levels were investigated in six normal mucosas, six adenomas and 30 MSI and MSS carcinomas. Sixty eight genes with tumor‐specific hypermethylation were identified (p < 0.005). Identified hypermethylated sites were validated in an independent sample set of eight normal mucosas, 12 adenomas, 40 MSS and nine MSI cancer samples. The methylation patterns of 15 selected genes, hypermethylated in adenomas and carcinomas (FLI1, ST6GALNAC5, TWIST1, ADHFE1, JAM2, IRF4, CNRIP1, NRG1 and EYA4), in carcinomas only (ABHD9, AOX1 and RERG), or in MSI but not MSS carcinomas (RAMP2, DSC3 and MLH1) were validated using MS‐HRM. Four of these genes (MLH1, AOX1, EYA4 and TWIST1) had previously been reported to be hypermethylated in CRC. Eleven genes, not previously known to be affected by CRC specific hypermethylation, were identified and validated. Inverse correlation to gene expression was observed for six of the 15 genes with Spearman correlation coefficients ranging from −0.39 to −0.60. For six of these genes the altered methylation patterns had a profound transcriptional association, indicating that methylation of these genes may play a direct regulatory role. The hypermethylation changes often occurred already in adenomas, indicating that they may be used as biomarkers for early detection of CRC.</description><identifier>ISSN: 0020-7136</identifier><identifier>ISSN: 1097-0215</identifier><identifier>EISSN: 1097-0215</identifier><identifier>DOI: 10.1002/ijc.25951</identifier><identifier>PMID: 21400501</identifier><identifier>CODEN: IJCNAW</identifier><language>eng</language><publisher>Hoboken: Wiley Subscription Services, Inc., A Wiley Company</publisher><subject>Adenoma ; Adenoma - genetics ; Aged ; Biological and medical sciences ; biomarkers ; Cancer ; Carcinoma ; Carcinoma - genetics ; Colorectal cancer ; Colorectal carcinoma ; Colorectal Neoplasms - genetics ; CpG islands ; CpG Islands - genetics ; DNA Methylation ; Exons ; Gastroenterology. Liver. Pancreas. Abdomen ; gene expression ; genome‐wide ; Humans ; Interferon regulatory factor 4 ; Male ; Medical sciences ; Melting ; microarray ; Middle Aged ; MLH1 protein ; Mucosa ; Neuregulin-1 - metabolism ; Receptor activity modifying proteins ; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus ; Transcription ; Tumors</subject><ispartof>International journal of cancer, 2011-12, Vol.129 (12), p.2855-2866</ispartof><rights>Copyright © 2011 UICC</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2011 UICC.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4881-85d3c56b3166ca986e2b58d7fafec82b32b4373530b70872569e5166e3a804d83</citedby><cites>FETCH-LOGICAL-c4881-85d3c56b3166ca986e2b58d7fafec82b32b4373530b70872569e5166e3a804d83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fijc.25951$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fijc.25951$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=24764990$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21400501$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Øster, Bodil</creatorcontrib><creatorcontrib>Thorsen, Kasper</creatorcontrib><creatorcontrib>Lamy, Philippe</creatorcontrib><creatorcontrib>Wojdacz, Tomasz K.</creatorcontrib><creatorcontrib>Hansen, Lise Lotte</creatorcontrib><creatorcontrib>Birkenkamp‐Demtröder, Karin</creatorcontrib><creatorcontrib>Sørensen, Karina D.</creatorcontrib><creatorcontrib>Laurberg, Søren</creatorcontrib><creatorcontrib>Ørntoft, Torben F.</creatorcontrib><creatorcontrib>Andersen, Claus L.</creatorcontrib><title>Identification and validation of highly frequent CpG island hypermethylation in colorectal adenomas and carcinomas</title><title>International journal of cancer</title><addtitle>Int J Cancer</addtitle><description>In our study, whole‐genome methylation arrays were applied to identify novel genes with tumor specific DNA methylation of promoter CpG islands in pre‐malignant and malignant colorectal lesions. Using a combination of Illumina HumanMethylation27 beadchips, Methylation‐Sensitive High Resolution Melting (MS‐HRM) analysis, and Exon arrays (Affymetrix) the DNA methylation pattern of ∼14,000 genes and their transcript levels were investigated in six normal mucosas, six adenomas and 30 MSI and MSS carcinomas. Sixty eight genes with tumor‐specific hypermethylation were identified (p < 0.005). Identified hypermethylated sites were validated in an independent sample set of eight normal mucosas, 12 adenomas, 40 MSS and nine MSI cancer samples. The methylation patterns of 15 selected genes, hypermethylated in adenomas and carcinomas (FLI1, ST6GALNAC5, TWIST1, ADHFE1, JAM2, IRF4, CNRIP1, NRG1 and EYA4), in carcinomas only (ABHD9, AOX1 and RERG), or in MSI but not MSS carcinomas (RAMP2, DSC3 and MLH1) were validated using MS‐HRM. Four of these genes (MLH1, AOX1, EYA4 and TWIST1) had previously been reported to be hypermethylated in CRC. Eleven genes, not previously known to be affected by CRC specific hypermethylation, were identified and validated. Inverse correlation to gene expression was observed for six of the 15 genes with Spearman correlation coefficients ranging from −0.39 to −0.60. For six of these genes the altered methylation patterns had a profound transcriptional association, indicating that methylation of these genes may play a direct regulatory role. The hypermethylation changes often occurred already in adenomas, indicating that they may be used as biomarkers for early detection of CRC.</description><subject>Adenoma</subject><subject>Adenoma - genetics</subject><subject>Aged</subject><subject>Biological and medical sciences</subject><subject>biomarkers</subject><subject>Cancer</subject><subject>Carcinoma</subject><subject>Carcinoma - genetics</subject><subject>Colorectal cancer</subject><subject>Colorectal carcinoma</subject><subject>Colorectal Neoplasms - genetics</subject><subject>CpG islands</subject><subject>CpG Islands - genetics</subject><subject>DNA Methylation</subject><subject>Exons</subject><subject>Gastroenterology. Liver. Pancreas. Abdomen</subject><subject>gene expression</subject><subject>genome‐wide</subject><subject>Humans</subject><subject>Interferon regulatory factor 4</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Melting</subject><subject>microarray</subject><subject>Middle Aged</subject><subject>MLH1 protein</subject><subject>Mucosa</subject><subject>Neuregulin-1 - metabolism</subject><subject>Receptor activity modifying proteins</subject><subject>Stomach. Duodenum. Small intestine. Colon. Rectum. Anus</subject><subject>Transcription</subject><subject>Tumors</subject><issn>0020-7136</issn><issn>1097-0215</issn><issn>1097-0215</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp90bFOwzAQBmALgaAUBl4AZUHAkPZsx4kzoghKUSUWmCPHcagrJyl2Csrb4zYFJpiskz_9d7pD6ALDBAOQqV7JCWEpwwdohCFNQiCYHaKR_4MwwTQ-QafOrQAwZhAdoxOCIwAGeITsvFRNpystRafbJhBNGXwIo8uhbKtgqd-Wpg8qq943ngbZehZoZ7Zw2a-VrVW37M3AdRPI1rRWyU6YQPjothZuFyqFlXpXnqGjShinzvfvGL0-3L9kj-HieTbP7hahjDjHIWcllSwuKI5jKVIeK1IwXiaVqJTkpKCkiGhCGYUiAZ4QFqeKeauo4BCVnI7R9ZC7tq0f3XV5rZ1Uxo-u2o3LU_DLwxxjL2_-ldjvkVNOOPP0dqDSts5ZVeVrq2the4_y7TFyf4x8dwxvL_exm6JW5Y_83r4HV3sgnBSmsqKR2v26KImjNAXvpoP71Eb1f3fM50_Z0PoLiYOgfg</recordid><startdate>20111215</startdate><enddate>20111215</enddate><creator>Øster, Bodil</creator><creator>Thorsen, Kasper</creator><creator>Lamy, Philippe</creator><creator>Wojdacz, Tomasz K.</creator><creator>Hansen, Lise Lotte</creator><creator>Birkenkamp‐Demtröder, Karin</creator><creator>Sørensen, Karina D.</creator><creator>Laurberg, Søren</creator><creator>Ørntoft, Torben F.</creator><creator>Andersen, Claus L.</creator><general>Wiley Subscription Services, Inc., A Wiley Company</general><general>Wiley-Blackwell</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TM</scope><scope>7X8</scope></search><sort><creationdate>20111215</creationdate><title>Identification and validation of highly frequent CpG island hypermethylation in colorectal adenomas and carcinomas</title><author>Øster, Bodil ; Thorsen, Kasper ; Lamy, Philippe ; Wojdacz, Tomasz K. ; Hansen, Lise Lotte ; Birkenkamp‐Demtröder, Karin ; Sørensen, Karina D. ; Laurberg, Søren ; Ørntoft, Torben F. ; Andersen, Claus L.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4881-85d3c56b3166ca986e2b58d7fafec82b32b4373530b70872569e5166e3a804d83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Adenoma</topic><topic>Adenoma - genetics</topic><topic>Aged</topic><topic>Biological and medical sciences</topic><topic>biomarkers</topic><topic>Cancer</topic><topic>Carcinoma</topic><topic>Carcinoma - genetics</topic><topic>Colorectal cancer</topic><topic>Colorectal carcinoma</topic><topic>Colorectal Neoplasms - genetics</topic><topic>CpG islands</topic><topic>CpG Islands - genetics</topic><topic>DNA Methylation</topic><topic>Exons</topic><topic>Gastroenterology. Liver. Pancreas. Abdomen</topic><topic>gene expression</topic><topic>genome‐wide</topic><topic>Humans</topic><topic>Interferon regulatory factor 4</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Melting</topic><topic>microarray</topic><topic>Middle Aged</topic><topic>MLH1 protein</topic><topic>Mucosa</topic><topic>Neuregulin-1 - metabolism</topic><topic>Receptor activity modifying proteins</topic><topic>Stomach. Duodenum. Small intestine. Colon. Rectum. Anus</topic><topic>Transcription</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Øster, Bodil</creatorcontrib><creatorcontrib>Thorsen, Kasper</creatorcontrib><creatorcontrib>Lamy, Philippe</creatorcontrib><creatorcontrib>Wojdacz, Tomasz K.</creatorcontrib><creatorcontrib>Hansen, Lise Lotte</creatorcontrib><creatorcontrib>Birkenkamp‐Demtröder, Karin</creatorcontrib><creatorcontrib>Sørensen, Karina D.</creatorcontrib><creatorcontrib>Laurberg, Søren</creatorcontrib><creatorcontrib>Ørntoft, Torben F.</creatorcontrib><creatorcontrib>Andersen, Claus L.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>International journal of cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Øster, Bodil</au><au>Thorsen, Kasper</au><au>Lamy, Philippe</au><au>Wojdacz, Tomasz K.</au><au>Hansen, Lise Lotte</au><au>Birkenkamp‐Demtröder, Karin</au><au>Sørensen, Karina D.</au><au>Laurberg, Søren</au><au>Ørntoft, Torben F.</au><au>Andersen, Claus L.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification and validation of highly frequent CpG island hypermethylation in colorectal adenomas and carcinomas</atitle><jtitle>International journal of cancer</jtitle><addtitle>Int J Cancer</addtitle><date>2011-12-15</date><risdate>2011</risdate><volume>129</volume><issue>12</issue><spage>2855</spage><epage>2866</epage><pages>2855-2866</pages><issn>0020-7136</issn><issn>1097-0215</issn><eissn>1097-0215</eissn><coden>IJCNAW</coden><abstract>In our study, whole‐genome methylation arrays were applied to identify novel genes with tumor specific DNA methylation of promoter CpG islands in pre‐malignant and malignant colorectal lesions. Using a combination of Illumina HumanMethylation27 beadchips, Methylation‐Sensitive High Resolution Melting (MS‐HRM) analysis, and Exon arrays (Affymetrix) the DNA methylation pattern of ∼14,000 genes and their transcript levels were investigated in six normal mucosas, six adenomas and 30 MSI and MSS carcinomas. Sixty eight genes with tumor‐specific hypermethylation were identified (p < 0.005). Identified hypermethylated sites were validated in an independent sample set of eight normal mucosas, 12 adenomas, 40 MSS and nine MSI cancer samples. The methylation patterns of 15 selected genes, hypermethylated in adenomas and carcinomas (FLI1, ST6GALNAC5, TWIST1, ADHFE1, JAM2, IRF4, CNRIP1, NRG1 and EYA4), in carcinomas only (ABHD9, AOX1 and RERG), or in MSI but not MSS carcinomas (RAMP2, DSC3 and MLH1) were validated using MS‐HRM. Four of these genes (MLH1, AOX1, EYA4 and TWIST1) had previously been reported to be hypermethylated in CRC. Eleven genes, not previously known to be affected by CRC specific hypermethylation, were identified and validated. Inverse correlation to gene expression was observed for six of the 15 genes with Spearman correlation coefficients ranging from −0.39 to −0.60. For six of these genes the altered methylation patterns had a profound transcriptional association, indicating that methylation of these genes may play a direct regulatory role. The hypermethylation changes often occurred already in adenomas, indicating that they may be used as biomarkers for early detection of CRC.</abstract><cop>Hoboken</cop><pub>Wiley Subscription Services, Inc., A Wiley Company</pub><pmid>21400501</pmid><doi>10.1002/ijc.25951</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Adenoma Adenoma - genetics Aged Biological and medical sciences biomarkers Cancer Carcinoma Carcinoma - genetics Colorectal cancer Colorectal carcinoma Colorectal Neoplasms - genetics CpG islands CpG Islands - genetics DNA Methylation Exons Gastroenterology. Liver. Pancreas. Abdomen gene expression genome‐wide Humans Interferon regulatory factor 4 Male Medical sciences Melting microarray Middle Aged MLH1 protein Mucosa Neuregulin-1 - metabolism Receptor activity modifying proteins Stomach. Duodenum. Small intestine. Colon. Rectum. Anus Transcription Tumors |
title | Identification and validation of highly frequent CpG island hypermethylation in colorectal adenomas and carcinomas |
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