Methylation of L1RE1, RARB, and RASSF1 function as possible biomarkers for the differential diagnosis of lung cancer
Lung cancer is the major cause of cancer-related deaths worldwide. Differential diagnosis can be difficult, especially when only small samples are available. Epigenetic changes are frequently tissue-specific events in carcinogenesis and hence may serve as diagnostic biomarkers. 138 representative fo...
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| creator | Walter, R F H Rozynek, P Casjens, S Werner, R Mairinger, F D Speel, E J M Zur Hausen, A Meier, S Wohlschlaeger, J Theegarten, D Behrens, T Schmid, K W Brüning, T Johnen, G |
| description | Lung cancer is the major cause of cancer-related deaths worldwide. Differential diagnosis can be difficult, especially when only small samples are available. Epigenetic changes are frequently tissue-specific events in carcinogenesis and hence may serve as diagnostic biomarkers.
138 representative formalin-fixed, paraffin-embedded (FFPE) tissues (116 lung cancer cases and 22 benign controls) were used for targeted DNA methylation analysis via pyrosequencing of ten literature-derived methylation markers (APC, CDH1, CDKN2A, EFEMP1, FHIT, L1RE1, MGMT, PTEN, RARB, and RASSF1). Methylation levels were analyzed with the Classification and Regression Tree Algorithm (CART), Conditional Interference Trees (ctree) and ROC. Validation was performed with additional 27 lung cancer cases and 38 benign controls. TCGA data for 282 lung cancer cases was included in the analysis.
CART and ctree analysis identified the combination of L1RE1 and RARB as well as L1RE1 and RASSF1 as independent methylation markers with high discriminative power between tumor and benign tissue (for each combination, 91% specificity and 100% sensitivity). L1RE1 methylation associated significantly with tumor type and grade (p |
| doi_str_mv | 10.1371/journal.pone.0195716 |
| format | Article |
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138 representative formalin-fixed, paraffin-embedded (FFPE) tissues (116 lung cancer cases and 22 benign controls) were used for targeted DNA methylation analysis via pyrosequencing of ten literature-derived methylation markers (APC, CDH1, CDKN2A, EFEMP1, FHIT, L1RE1, MGMT, PTEN, RARB, and RASSF1). Methylation levels were analyzed with the Classification and Regression Tree Algorithm (CART), Conditional Interference Trees (ctree) and ROC. Validation was performed with additional 27 lung cancer cases and 38 benign controls. TCGA data for 282 lung cancer cases was included in the analysis.
CART and ctree analysis identified the combination of L1RE1 and RARB as well as L1RE1 and RASSF1 as independent methylation markers with high discriminative power between tumor and benign tissue (for each combination, 91% specificity and 100% sensitivity). L1RE1 methylation associated significantly with tumor type and grade (p<0.001) with highest methylation in the control group. The opposite was found for RARB (p<0.001). RASSF1 methylation increased with tumor type and grade (p<0.001) with strongest methylation in neuroendocrine tumors (NET).
Hypomethylation of L1RE1 is frequent in tumors compared to benign controls and associates with higher grade, whereas increasing methylation of RARB is an independent marker for tumors and higher grade. RASSF1 hypermethylation was frequent in tumors and most prominent in NET making it an auxiliary marker for separation of NSCLC and NET. L1RE1 in combination with either RARB or RASSF1 could function as biomarkers for separating lung cancer and non-cancerous tissue and could be useful for samples of limited size such as biopsies.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0195716</identifier><identifier>PMID: 29851970</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adenomatous polyposis coli ; Benign ; Biology and life sciences ; Biomarkers ; Cancer ; Carcinogenesis ; Carcinogens ; Causes of ; Cell adhesion & migration ; Deoxyribonucleic acid ; Developmental biology ; Diagnosis ; Diagnostic systems ; Differential diagnosis ; DNA ; DNA methylation ; E-cadherin ; Epigenetic inheritance ; Gene expression ; Genomes ; Genomics ; Health aspects ; Hospitals ; Lung cancer ; Lung diseases ; Medical diagnosis ; Medical research ; Medicine ; Medicine and Health Sciences ; Methylation ; Neuroendocrine tumors ; Non-small cell lung carcinoma ; Paraffin ; Pathology ; Physical Sciences ; Plant tissues ; Prevention ; PTEN protein ; Regression analysis ; Tumors</subject><ispartof>PloS one, 2018-05, Vol.13 (5), p.e0195716</ispartof><rights>COPYRIGHT 2018 Public Library of Science</rights><rights>2018 Walter et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://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>2018 Walter et al 2018 Walter et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-a89dba5e775d4c0db67b1c7effa7b6cd81e2b77ffadf27c71d3791b5076fd54b3</citedby><cites>FETCH-LOGICAL-c692t-a89dba5e775d4c0db67b1c7effa7b6cd81e2b77ffadf27c71d3791b5076fd54b3</cites><orcidid>0000-0003-3725-7064</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5978787/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5978787/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,729,782,786,866,887,2106,2932,23875,27933,27934,53800,53802</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29851970$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Guo, Nancy Lan</contributor><creatorcontrib>Walter, R F H</creatorcontrib><creatorcontrib>Rozynek, P</creatorcontrib><creatorcontrib>Casjens, S</creatorcontrib><creatorcontrib>Werner, R</creatorcontrib><creatorcontrib>Mairinger, F D</creatorcontrib><creatorcontrib>Speel, E J M</creatorcontrib><creatorcontrib>Zur Hausen, A</creatorcontrib><creatorcontrib>Meier, S</creatorcontrib><creatorcontrib>Wohlschlaeger, J</creatorcontrib><creatorcontrib>Theegarten, D</creatorcontrib><creatorcontrib>Behrens, T</creatorcontrib><creatorcontrib>Schmid, K W</creatorcontrib><creatorcontrib>Brüning, T</creatorcontrib><creatorcontrib>Johnen, G</creatorcontrib><title>Methylation of L1RE1, RARB, and RASSF1 function as possible biomarkers for the differential diagnosis of lung cancer</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Lung cancer is the major cause of cancer-related deaths worldwide. Differential diagnosis can be difficult, especially when only small samples are available. Epigenetic changes are frequently tissue-specific events in carcinogenesis and hence may serve as diagnostic biomarkers.
138 representative formalin-fixed, paraffin-embedded (FFPE) tissues (116 lung cancer cases and 22 benign controls) were used for targeted DNA methylation analysis via pyrosequencing of ten literature-derived methylation markers (APC, CDH1, CDKN2A, EFEMP1, FHIT, L1RE1, MGMT, PTEN, RARB, and RASSF1). Methylation levels were analyzed with the Classification and Regression Tree Algorithm (CART), Conditional Interference Trees (ctree) and ROC. Validation was performed with additional 27 lung cancer cases and 38 benign controls. TCGA data for 282 lung cancer cases was included in the analysis.
CART and ctree analysis identified the combination of L1RE1 and RARB as well as L1RE1 and RASSF1 as independent methylation markers with high discriminative power between tumor and benign tissue (for each combination, 91% specificity and 100% sensitivity). L1RE1 methylation associated significantly with tumor type and grade (p<0.001) with highest methylation in the control group. The opposite was found for RARB (p<0.001). RASSF1 methylation increased with tumor type and grade (p<0.001) with strongest methylation in neuroendocrine tumors (NET).
Hypomethylation of L1RE1 is frequent in tumors compared to benign controls and associates with higher grade, whereas increasing methylation of RARB is an independent marker for tumors and higher grade. RASSF1 hypermethylation was frequent in tumors and most prominent in NET making it an auxiliary marker for separation of NSCLC and NET. L1RE1 in combination with either RARB or RASSF1 could function as biomarkers for separating lung cancer and non-cancerous tissue and could be useful for samples of limited size such as biopsies.</description><subject>Adenomatous polyposis coli</subject><subject>Benign</subject><subject>Biology and life sciences</subject><subject>Biomarkers</subject><subject>Cancer</subject><subject>Carcinogenesis</subject><subject>Carcinogens</subject><subject>Causes of</subject><subject>Cell adhesion & migration</subject><subject>Deoxyribonucleic acid</subject><subject>Developmental biology</subject><subject>Diagnosis</subject><subject>Diagnostic systems</subject><subject>Differential diagnosis</subject><subject>DNA</subject><subject>DNA methylation</subject><subject>E-cadherin</subject><subject>Epigenetic inheritance</subject><subject>Gene expression</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Health aspects</subject><subject>Hospitals</subject><subject>Lung cancer</subject><subject>Lung diseases</subject><subject>Medical diagnosis</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Methylation</subject><subject>Neuroendocrine tumors</subject><subject>Non-small cell lung carcinoma</subject><subject>Paraffin</subject><subject>Pathology</subject><subject>Physical Sciences</subject><subject>Plant tissues</subject><subject>Prevention</subject><subject>PTEN protein</subject><subject>Regression 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of L1RE1, RARB, and RASSF1 function as possible biomarkers for the differential diagnosis of lung cancer</title><author>Walter, R F H ; Rozynek, P ; Casjens, S ; Werner, R ; Mairinger, F D ; Speel, E J M ; Zur Hausen, A ; Meier, S ; Wohlschlaeger, J ; Theegarten, D ; Behrens, T ; Schmid, K W ; Brüning, T ; Johnen, G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-a89dba5e775d4c0db67b1c7effa7b6cd81e2b77ffadf27c71d3791b5076fd54b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Adenomatous polyposis coli</topic><topic>Benign</topic><topic>Biology and life sciences</topic><topic>Biomarkers</topic><topic>Cancer</topic><topic>Carcinogenesis</topic><topic>Carcinogens</topic><topic>Causes of</topic><topic>Cell adhesion & migration</topic><topic>Deoxyribonucleic acid</topic><topic>Developmental biology</topic><topic>Diagnosis</topic><topic>Diagnostic 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Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Walter, R F H</au><au>Rozynek, P</au><au>Casjens, S</au><au>Werner, R</au><au>Mairinger, F D</au><au>Speel, E J M</au><au>Zur Hausen, A</au><au>Meier, S</au><au>Wohlschlaeger, J</au><au>Theegarten, D</au><au>Behrens, T</au><au>Schmid, K W</au><au>Brüning, T</au><au>Johnen, G</au><au>Guo, Nancy Lan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Methylation of L1RE1, RARB, and RASSF1 function as possible biomarkers for the differential diagnosis of lung cancer</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2018-05-31</date><risdate>2018</risdate><volume>13</volume><issue>5</issue><spage>e0195716</spage><pages>e0195716-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Lung cancer is the major cause of cancer-related deaths worldwide. Differential diagnosis can be difficult, especially when only small samples are available. Epigenetic changes are frequently tissue-specific events in carcinogenesis and hence may serve as diagnostic biomarkers.
138 representative formalin-fixed, paraffin-embedded (FFPE) tissues (116 lung cancer cases and 22 benign controls) were used for targeted DNA methylation analysis via pyrosequencing of ten literature-derived methylation markers (APC, CDH1, CDKN2A, EFEMP1, FHIT, L1RE1, MGMT, PTEN, RARB, and RASSF1). Methylation levels were analyzed with the Classification and Regression Tree Algorithm (CART), Conditional Interference Trees (ctree) and ROC. Validation was performed with additional 27 lung cancer cases and 38 benign controls. TCGA data for 282 lung cancer cases was included in the analysis.
CART and ctree analysis identified the combination of L1RE1 and RARB as well as L1RE1 and RASSF1 as independent methylation markers with high discriminative power between tumor and benign tissue (for each combination, 91% specificity and 100% sensitivity). L1RE1 methylation associated significantly with tumor type and grade (p<0.001) with highest methylation in the control group. The opposite was found for RARB (p<0.001). RASSF1 methylation increased with tumor type and grade (p<0.001) with strongest methylation in neuroendocrine tumors (NET).
Hypomethylation of L1RE1 is frequent in tumors compared to benign controls and associates with higher grade, whereas increasing methylation of RARB is an independent marker for tumors and higher grade. RASSF1 hypermethylation was frequent in tumors and most prominent in NET making it an auxiliary marker for separation of NSCLC and NET. L1RE1 in combination with either RARB or RASSF1 could function as biomarkers for separating lung cancer and non-cancerous tissue and could be useful for samples of limited size such as biopsies.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>29851970</pmid><doi>10.1371/journal.pone.0195716</doi><tpages>e0195716</tpages><orcidid>https://orcid.org/0000-0003-3725-7064</orcidid><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_2047867261 |
| source | Public Library of Science (PLoS) Journals Open Access; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Adenomatous polyposis coli Benign Biology and life sciences Biomarkers Cancer Carcinogenesis Carcinogens Causes of Cell adhesion & migration Deoxyribonucleic acid Developmental biology Diagnosis Diagnostic systems Differential diagnosis DNA DNA methylation E-cadherin Epigenetic inheritance Gene expression Genomes Genomics Health aspects Hospitals Lung cancer Lung diseases Medical diagnosis Medical research Medicine Medicine and Health Sciences Methylation Neuroendocrine tumors Non-small cell lung carcinoma Paraffin Pathology Physical Sciences Plant tissues Prevention PTEN protein Regression analysis Tumors |
| title | Methylation of L1RE1, RARB, and RASSF1 function as possible biomarkers for the differential diagnosis of lung cancer |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-11-30T02%3A47%3A10IST&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=Methylation%20of%20L1RE1,%20RARB,%20and%20RASSF1%20function%20as%20possible%20biomarkers%20for%20the%20differential%20diagnosis%20of%20lung%20cancer&rft.jtitle=PloS%20one&rft.au=Walter,%20R%20F%20H&rft.date=2018-05-31&rft.volume=13&rft.issue=5&rft.spage=e0195716&rft.pages=e0195716-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0195716&rft_dat=%3Cgale_plos_%3EA540977570%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=2047867261&rft_id=info:pmid/29851970&rft_galeid=A540977570&rft_doaj_id=oai_doaj_org_article_769bd767af624da4b97f83549547c7bd&rfr_iscdi=true |