DNA methylation changes in atypical adenomatous hyperplasia, adenocarcinoma in situ, and lung adenocarcinoma
Aberrant DNA methylation is common in lung adenocarcinoma, but its timing in the phases of tumor development is largely unknown. Delineating when abnormal DNA methylation arises may provide insight into the natural history of lung adenocarcinoma and the role that DNA methylation alterations play in...
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| description | Aberrant DNA methylation is common in lung adenocarcinoma, but its timing in the phases of tumor development is largely unknown. Delineating when abnormal DNA methylation arises may provide insight into the natural history of lung adenocarcinoma and the role that DNA methylation alterations play in tumor formation.
We used MethyLight, a sensitive real-time PCR-based quantitative method, to analyze DNA methylation levels at 15 CpG islands that are frequently methylated in lung adenocarcinoma and that we had flagged as potential markers for non-invasive detection. We also used two repeat probes as indicators of global DNA hypomethylation. We examined DNA methylation in 249 tissue samples from 93 subjects, spanning the putative spectrum of peripheral lung adenocarcinoma development: histologically normal adjacent non-tumor lung, atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS, formerly known as bronchioloalveolar carcinoma), and invasive lung adenocarcinoma. Comparison of DNA methylation levels between the lesion types suggests that DNA hypermethylation of distinct loci occurs at different time points during the development of lung adenocarcinoma. DNA methylation at CDKN2A ex2 and PTPRN2 is already significantly elevated in AAH, while CpG islands at 2C35, EYA4, HOXA1, HOXA11, NEUROD1, NEUROD2 and TMEFF2 are significantly hypermethylated in AIS. In contrast, hypermethylation at CDH13, CDX2, OPCML, RASSF1, SFRP1 and TWIST1 and global DNA hypomethylation appear to be present predominantly in invasive cancer.
The gradual increase in DNA methylation seen for numerous loci in progressively more transformed lesions supports the model in which AAH and AIS are sequential stages in the development of lung adenocarcinoma. The demarcation of DNA methylation changes characteristic for AAH, AIS and adenocarcinoma begins to lay out a possible roadmap for aberrant DNA methylation events in tumor development. In addition, it identifies which DNA methylation changes might be used as molecular markers for the detection of preinvasive lesions. |
| doi_str_mv | 10.1371/journal.pone.0021443 |
| format | Article |
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We used MethyLight, a sensitive real-time PCR-based quantitative method, to analyze DNA methylation levels at 15 CpG islands that are frequently methylated in lung adenocarcinoma and that we had flagged as potential markers for non-invasive detection. We also used two repeat probes as indicators of global DNA hypomethylation. We examined DNA methylation in 249 tissue samples from 93 subjects, spanning the putative spectrum of peripheral lung adenocarcinoma development: histologically normal adjacent non-tumor lung, atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS, formerly known as bronchioloalveolar carcinoma), and invasive lung adenocarcinoma. Comparison of DNA methylation levels between the lesion types suggests that DNA hypermethylation of distinct loci occurs at different time points during the development of lung adenocarcinoma. DNA methylation at CDKN2A ex2 and PTPRN2 is already significantly elevated in AAH, while CpG islands at 2C35, EYA4, HOXA1, HOXA11, NEUROD1, NEUROD2 and TMEFF2 are significantly hypermethylated in AIS. In contrast, hypermethylation at CDH13, CDX2, OPCML, RASSF1, SFRP1 and TWIST1 and global DNA hypomethylation appear to be present predominantly in invasive cancer.
The gradual increase in DNA methylation seen for numerous loci in progressively more transformed lesions supports the model in which AAH and AIS are sequential stages in the development of lung adenocarcinoma. The demarcation of DNA methylation changes characteristic for AAH, AIS and adenocarcinoma begins to lay out a possible roadmap for aberrant DNA methylation events in tumor development. In addition, it identifies which DNA methylation changes might be used as molecular markers for the detection of preinvasive lesions.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0021443</identifier><identifier>PMID: 21731750</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Aberration ; Adenocarcinoma ; Adenocarcinoma - genetics ; Adenocarcinoma - pathology ; Adenocarcinoma of Lung ; Adenoma - genetics ; Adenoma - pathology ; Beta2 protein ; Biochemistry ; Biology ; Cancer genetics ; CDX2 protein ; CpG islands ; Deoxyribonucleic acid ; Departments ; DNA ; DNA methylation ; DNA Methylation - genetics ; DNA probes ; Epigenetics ; Frizzled-related protein 1 ; Genes ; Genetic Loci - genetics ; Genetic research ; HOXA1 protein ; Humans ; Hyperplasia ; Hyperplasia - genetics ; Hyperplasia - pathology ; Islands ; Lesions ; Loci ; Lung - pathology ; Lung cancer ; Lung carcinoma ; Lung Neoplasms - genetics ; Lung Neoplasms - pathology ; Markers ; Medical imaging ; Medical prognosis ; Medical screening ; Medicine ; Methylation ; Molecular biology ; Mortality ; Precancerous Conditions - genetics ; Precancerous Conditions - pathology ; Preventive medicine ; Proteins ; Studies ; Surgery ; Tumors</subject><ispartof>PloS one, 2011-06, Vol.6 (6), p.e21443-e21443</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>2011 Selamat et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Selamat et al. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c757t-81f03d27954e54d209241d182084f632bb9d7c5303400eebbd57426021ec74593</citedby><cites>FETCH-LOGICAL-c757t-81f03d27954e54d209241d182084f632bb9d7c5303400eebbd57426021ec74593</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3121768/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3121768/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21731750$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Selamat, Suhaida A</creatorcontrib><creatorcontrib>Galler, Janice S</creatorcontrib><creatorcontrib>Joshi, Amit D</creatorcontrib><creatorcontrib>Fyfe, M Nicky</creatorcontrib><creatorcontrib>Campan, Mihaela</creatorcontrib><creatorcontrib>Siegmund, Kimberly D</creatorcontrib><creatorcontrib>Kerr, Keith M</creatorcontrib><creatorcontrib>Laird-Offringa, Ite A</creatorcontrib><title>DNA methylation changes in atypical adenomatous hyperplasia, adenocarcinoma in situ, and lung adenocarcinoma</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Aberrant DNA methylation is common in lung adenocarcinoma, but its timing in the phases of tumor development is largely unknown. Delineating when abnormal DNA methylation arises may provide insight into the natural history of lung adenocarcinoma and the role that DNA methylation alterations play in tumor formation.
We used MethyLight, a sensitive real-time PCR-based quantitative method, to analyze DNA methylation levels at 15 CpG islands that are frequently methylated in lung adenocarcinoma and that we had flagged as potential markers for non-invasive detection. We also used two repeat probes as indicators of global DNA hypomethylation. We examined DNA methylation in 249 tissue samples from 93 subjects, spanning the putative spectrum of peripheral lung adenocarcinoma development: histologically normal adjacent non-tumor lung, atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS, formerly known as bronchioloalveolar carcinoma), and invasive lung adenocarcinoma. Comparison of DNA methylation levels between the lesion types suggests that DNA hypermethylation of distinct loci occurs at different time points during the development of lung adenocarcinoma. DNA methylation at CDKN2A ex2 and PTPRN2 is already significantly elevated in AAH, while CpG islands at 2C35, EYA4, HOXA1, HOXA11, NEUROD1, NEUROD2 and TMEFF2 are significantly hypermethylated in AIS. In contrast, hypermethylation at CDH13, CDX2, OPCML, RASSF1, SFRP1 and TWIST1 and global DNA hypomethylation appear to be present predominantly in invasive cancer.
The gradual increase in DNA methylation seen for numerous loci in progressively more transformed lesions supports the model in which AAH and AIS are sequential stages in the development of lung adenocarcinoma. The demarcation of DNA methylation changes characteristic for AAH, AIS and adenocarcinoma begins to lay out a possible roadmap for aberrant DNA methylation events in tumor development. In addition, it identifies which DNA methylation changes might be used as molecular markers for the detection of preinvasive lesions.</description><subject>Aberration</subject><subject>Adenocarcinoma</subject><subject>Adenocarcinoma - genetics</subject><subject>Adenocarcinoma - pathology</subject><subject>Adenocarcinoma of Lung</subject><subject>Adenoma - genetics</subject><subject>Adenoma - pathology</subject><subject>Beta2 protein</subject><subject>Biochemistry</subject><subject>Biology</subject><subject>Cancer genetics</subject><subject>CDX2 protein</subject><subject>CpG islands</subject><subject>Deoxyribonucleic acid</subject><subject>Departments</subject><subject>DNA</subject><subject>DNA methylation</subject><subject>DNA Methylation - genetics</subject><subject>DNA probes</subject><subject>Epigenetics</subject><subject>Frizzled-related protein 1</subject><subject>Genes</subject><subject>Genetic Loci - genetics</subject><subject>Genetic research</subject><subject>HOXA1 protein</subject><subject>Humans</subject><subject>Hyperplasia</subject><subject>Hyperplasia - genetics</subject><subject>Hyperplasia - pathology</subject><subject>Islands</subject><subject>Lesions</subject><subject>Loci</subject><subject>Lung - pathology</subject><subject>Lung cancer</subject><subject>Lung carcinoma</subject><subject>Lung Neoplasms - genetics</subject><subject>Lung Neoplasms - pathology</subject><subject>Markers</subject><subject>Medical imaging</subject><subject>Medical prognosis</subject><subject>Medical screening</subject><subject>Medicine</subject><subject>Methylation</subject><subject>Molecular biology</subject><subject>Mortality</subject><subject>Precancerous Conditions - genetics</subject><subject>Precancerous Conditions - pathology</subject><subject>Preventive medicine</subject><subject>Proteins</subject><subject>Studies</subject><subject>Surgery</subject><subject>Tumors</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk2uL1DAUhoso7rr6D0QLgiI4Y25t2i_CsN4GFhe8fQ2nadpmySS1ScX596ZOd5ku-0EaaDnned_TnOQkyVOM1phy_PbKjYMFs-6dVWuECGaM3ktOcUnJKieI3j_6PkkeeX-FUEaLPH-YnBDMKeYZOk3M-y-bdKdCtzcQtLOp7MC2yqfaphD2vZZgUqiVdTsIbvRpt-_V0BvwGt4cEhIGqaf8pPE6jDFu69SMtr0FPE4eNGC8ejK_z5IfHz98P_-8urj8tD3fXKwkz3hYFbhBtCa8zJjKWE1QSRiucUFQwZqckqoqay4ziihDSKmqqjPOSB5boCRnWUnPkucH3944L-ZGeYEpYgXGvESR2B6I2sGV6Ae9g2EvHGjxL-CGVsAQtDRKVERVmOUSGmgYAyh5RpQsEAKWNxnj0evdXG2sdqqWyoYBzMJ0mbG6E637LSiO55AX0eDVbDC4X6PyQey0l8oYsCq2XBQ8Y0VZcBrJF7fIuzc3Uy3E_9e2cbGsnDzFhsWCxbQitb6Dik-tdlrGS9XoGF8IXi8EkQnqT2hh9F5sv339f_by55J9ecR2CkzovDPjdB39EmQHUA7O-0E1Nz3GSEwzcd0NMc2EmGciyp4dn8-N6HoI6F95SQa9</recordid><startdate>20110623</startdate><enddate>20110623</enddate><creator>Selamat, Suhaida A</creator><creator>Galler, Janice S</creator><creator>Joshi, Amit D</creator><creator>Fyfe, M Nicky</creator><creator>Campan, Mihaela</creator><creator>Siegmund, Kimberly D</creator><creator>Kerr, Keith M</creator><creator>Laird-Offringa, Ite A</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20110623</creationdate><title>DNA methylation changes in atypical adenomatous hyperplasia, adenocarcinoma in situ, and lung adenocarcinoma</title><author>Selamat, Suhaida A ; Galler, Janice S ; Joshi, Amit D ; Fyfe, M Nicky ; Campan, Mihaela ; Siegmund, Kimberly D ; Kerr, Keith M ; Laird-Offringa, Ite A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c757t-81f03d27954e54d209241d182084f632bb9d7c5303400eebbd57426021ec74593</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Aberration</topic><topic>Adenocarcinoma</topic><topic>Adenocarcinoma - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Selamat, Suhaida A</au><au>Galler, Janice S</au><au>Joshi, Amit D</au><au>Fyfe, M Nicky</au><au>Campan, Mihaela</au><au>Siegmund, Kimberly D</au><au>Kerr, Keith M</au><au>Laird-Offringa, Ite A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>DNA methylation changes in atypical adenomatous hyperplasia, adenocarcinoma in situ, and lung adenocarcinoma</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2011-06-23</date><risdate>2011</risdate><volume>6</volume><issue>6</issue><spage>e21443</spage><epage>e21443</epage><pages>e21443-e21443</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Aberrant DNA methylation is common in lung adenocarcinoma, but its timing in the phases of tumor development is largely unknown. Delineating when abnormal DNA methylation arises may provide insight into the natural history of lung adenocarcinoma and the role that DNA methylation alterations play in tumor formation.
We used MethyLight, a sensitive real-time PCR-based quantitative method, to analyze DNA methylation levels at 15 CpG islands that are frequently methylated in lung adenocarcinoma and that we had flagged as potential markers for non-invasive detection. We also used two repeat probes as indicators of global DNA hypomethylation. We examined DNA methylation in 249 tissue samples from 93 subjects, spanning the putative spectrum of peripheral lung adenocarcinoma development: histologically normal adjacent non-tumor lung, atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS, formerly known as bronchioloalveolar carcinoma), and invasive lung adenocarcinoma. Comparison of DNA methylation levels between the lesion types suggests that DNA hypermethylation of distinct loci occurs at different time points during the development of lung adenocarcinoma. DNA methylation at CDKN2A ex2 and PTPRN2 is already significantly elevated in AAH, while CpG islands at 2C35, EYA4, HOXA1, HOXA11, NEUROD1, NEUROD2 and TMEFF2 are significantly hypermethylated in AIS. In contrast, hypermethylation at CDH13, CDX2, OPCML, RASSF1, SFRP1 and TWIST1 and global DNA hypomethylation appear to be present predominantly in invasive cancer.
The gradual increase in DNA methylation seen for numerous loci in progressively more transformed lesions supports the model in which AAH and AIS are sequential stages in the development of lung adenocarcinoma. The demarcation of DNA methylation changes characteristic for AAH, AIS and adenocarcinoma begins to lay out a possible roadmap for aberrant DNA methylation events in tumor development. In addition, it identifies which DNA methylation changes might be used as molecular markers for the detection of preinvasive lesions.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>21731750</pmid><doi>10.1371/journal.pone.0021443</doi><tpages>e21443</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Aberration Adenocarcinoma Adenocarcinoma - genetics Adenocarcinoma - pathology Adenocarcinoma of Lung Adenoma - genetics Adenoma - pathology Beta2 protein Biochemistry Biology Cancer genetics CDX2 protein CpG islands Deoxyribonucleic acid Departments DNA DNA methylation DNA Methylation - genetics DNA probes Epigenetics Frizzled-related protein 1 Genes Genetic Loci - genetics Genetic research HOXA1 protein Humans Hyperplasia Hyperplasia - genetics Hyperplasia - pathology Islands Lesions Loci Lung - pathology Lung cancer Lung carcinoma Lung Neoplasms - genetics Lung Neoplasms - pathology Markers Medical imaging Medical prognosis Medical screening Medicine Methylation Molecular biology Mortality Precancerous Conditions - genetics Precancerous Conditions - pathology Preventive medicine Proteins Studies Surgery Tumors |
| title | DNA methylation changes in atypical adenomatous hyperplasia, adenocarcinoma in situ, and lung adenocarcinoma |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-10T06%3A03%3A11IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=DNA%20methylation%20changes%20in%20atypical%20adenomatous%20hyperplasia,%20adenocarcinoma%20in%20situ,%20and%20lung%20adenocarcinoma&rft.jtitle=PloS%20one&rft.au=Selamat,%20Suhaida%20A&rft.date=2011-06-23&rft.volume=6&rft.issue=6&rft.spage=e21443&rft.epage=e21443&rft.pages=e21443-e21443&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0021443&rft_dat=%3Cgale_plos_%3EA476886886%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1304811790&rft_id=info:pmid/21731750&rft_galeid=A476886886&rft_doaj_id=oai_doaj_org_article_b2eb146cafaf44aa9752ec800a46f547&rfr_iscdi=true |