Frequent hypermethylation of the RASSF1A gene in prostate cancer

<!DOCTYPE html> <html lang="en" class="grade-c"> <head> <title>Frequent hypermethylation of the RASSF1A gene in prostate cancer | Oncogene</title> <link rel="alternate" type="application/rss+xml" href="https://www.nature.com/onc.rss"/> <link rel="preconnect" href="https://cmp.nature.com" crossorigin> <meta http-equiv="X-UA-Compatible" content="IE=edge"> <meta name="applicable-device" content="pc,mobile"> <meta name="viewport" content="width=device-width,initial-scale=1.0,maximum-scale=5,user-scalable=yes"> <meta name="360-site-verification" content="5a2dc4ab3fcb9b0393241ffbbb490480" /> <script data-test="dataLayer"> window.dataLayer = [{"content":{"category":{"contentType":"short report","legacy":{"webtrendsPrimaryArticleType":"research","webtrendsSubjectTerms":null,"webtrendsContentCategory":null,"webtrendsContentCollection":null,"webtrendsContentGroup":"Oncogene","webtrendsContentGroupType":null,"webtrendsContentSubGroup":"Short 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The CpG island promoter region of this gene is highly methylated in several human cancers, most notably in small cell lung cancer, breast cancer, and renal cell carcinoma. In this study, we have analysed the methylation status of RASSF1A in primary prostate tumors and in the prostate cancer cell line LNCaP. In total, 37 out of 52 tumors (71%) were methylated at the promoter region of RASSF1A. The relative frequency of methylation was higher in more aggressive tumors compared with less malignant tumors. For instance, tumors with a Gleason score of 7–10 (25 out of 30, 83%) were significantly more methylated compared with Gleason 4–6 tumors (11 out of 20, 55%, P=0.032, Fisher's exact test). Coincident with a hypermethylated promoter, transcripts of RASSF1A were missing in LNCaP cells. Expression of RASSF1A was restored with 5-aza-2′-deoxycytidine, a DNA methylation inhibitor. In conclusion, our data suggest that epigenetic inactivation of RASSF1A by methylation is a very common event in prostate cancer and might be involved in the progression of the disease. Testing for RASSF1A methylation should become useful in prostate cancer early detection and diagnosis and might aid prognosis by gauging the potential status of progression.","datePublished":"2002-10-02T00:00:00Z","dateModified":"2002-10-02T00:00:00Z","pageStart":"6835","pageEnd":"6840","sameAs":"https://doi.org/10.1038/sj.onc.1205814","keywords":["\n RASSF1A\n ","methylation","tumor suppressor gene","prostate cancer","Medicine/Public Health","general","Internal Medicine","Cell Biology","Human Genetics","Oncology","Apoptosis"],"image":["https://media.springernature.com/lw1200/springer-static/image/art%3A10.1038%2Fsj.onc.1205814/MediaObjects/41388_2002_Article_BF1205814_Fig1_HTML.jpg","https://media.springernature.com/lw1200/springer-static/image/art%3A10.1038%2Fsj.onc.1205814/MediaObjects/41388_2002_Article_BF1205814_Fig2_HTML.jpg","https://media.springernature.com/lw1200/springer-static/image/art%3A10.1038%2Fsj.onc.1205814/MediaObjects/41388_2002_Article_BF1205814_Fig3_HTML.jpg"],"isPartOf":{"name":"Oncogene","issn":["1476-5594","0950-9232"],"volumeNumber":"21","@type":["Periodical","PublicationVolume"]},"publisher":{"name":"Nature Publishing Group UK","logo":{"url":"https://www.springernature.com/app-sn/public/images/logo-springernature.png","@type":"ImageObject"},"@type":"Organization"},"author":[{"name":"Limin Liu","affiliation":[{"name":"Beckman Research Institute, City of Hope Cancer Center","address":{"name":"Department of Biology, Beckman Research Institute, City of Hope Cancer Center, Duarte, USA","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Jung-Hoon Yoon","affiliation":[{"name":"Beckman Research Institute, City of Hope Cancer Center","address":{"name":"Department of Biology, Beckman Research Institute, City of Hope Cancer Center, Duarte, USA","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Reinhard Dammann","affiliation":[{"name":"Institut für Humangenetik und Medizinische Biologie, Martin-Luther-Universität Halle-Wittenberg","address":{"name":"Institut für Humangenetik und Medizinische Biologie, Martin-Luther-Universität Halle-Wittenberg, Germany","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Gerd P Pfeifer","affiliation":[{"name":"Beckman Research Institute, City of Hope Cancer Center","address":{"name":"Department of Biology, Beckman Research Institute, City of Hope Cancer Center, Duarte, USA","@type":"PostalAddress"},"@type":"Organization"}],"email":"gpfeifer@coh.org","@type":"Person"}],"isAccessibleForFree":false,"hasPart":{"isAccessibleForFree":false,"cssSelector":".main-content","@type":"WebPageElement"},"@type":"ScholarlyArticle"},"@context":"https://schema.org","@type":"WebPage"}</script> <link rel="canonical" href="https://www.nature.com/articles/1205814"> <meta name="journal_id" content="41388"/> <meta name="dc.title" content="Frequent hypermethylation of the RASSF1A gene in prostate cancer"/> <meta name="dc.source" content="Oncogene 2002 21:44"/> <meta name="dc.format" content="text/html"/> <meta name="dc.publisher" content="Nature Publishing Group"/> <meta name="dc.date" content="2002-10-02"/> <meta name="dc.type" content="OriginalPaper"/> <meta name="dc.language" content="En"/> <meta name="dc.copyright" content="2002 Macmillan Publishers Limited"/> <meta name="dc.rights" content="2002 Macmillan Publishers Limited"/> <meta name="dc.rightsAgent" content="journalpermissions@springernature.com"/> <meta name="dc.description" content="Recently, we have cloned and characterized the Ras association domain family 1A gene (RASSF1A) at 3p21.3, from which loss of genetic material is one of the most frequent events in several types of human solid tumors. The CpG island promoter region of this gene is highly methylated in several human cancers, most notably in small cell lung cancer, breast cancer, and renal cell carcinoma. In this study, we have analysed the methylation status of RASSF1A in primary prostate tumors and in the prostate cancer cell line LNCaP. In total, 37 out of 52 tumors (71%) were methylated at the promoter region of RASSF1A. The relative frequency of methylation was higher in more aggressive tumors compared with less malignant tumors. For instance, tumors with a Gleason score of 7–10 (25 out of 30, 83%) were significantly more methylated compared with Gleason 4–6 tumors (11 out of 20, 55%, P=0.032, Fisher's exact test). Coincident with a hypermethylated promoter, transcripts of RASSF1A were missing in LNCaP cells. Expression of RASSF1A was restored with 5-aza-2′-deoxycytidine, a DNA methylation inhibitor. 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The CpG island promoter region of this gene is highly methylated in several human cancers, most notably in small cell lung cancer, breast cancer, and renal cell carcinoma. In this study, we have analysed the methylation status of RASSF1A in primary prostate tumors and in the prostate cancer cell line LNCaP. In total, 37 out of 52 tumors (71%) were methylated at the promoter region of RASSF1A. The relative frequency of methylation was higher in more aggressive tumors compared with less malignant tumors. For instance, tumors with a Gleason score of 7–10 (25 out of 30, 83%) were significantly more methylated compared with Gleason 4–6 tumors (11 out of 20, 55%, P=0.032, Fisher's exact test). Coincident with a hypermethylated promoter, transcripts of RASSF1A were missing in LNCaP cells. Expression of RASSF1A was restored with 5-aza-2′-deoxycytidine, a DNA methylation inhibitor. 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id="breadcrumb3" itemprop="itemListElement" itemscope itemtype="https://schema.org/ListItem"> <span itemprop="name">article</span><meta itemprop="position" content="4"></li> </ol> </div> </nav> </div> <div class="u-container u-mt-32 u-mb-32 u-clearfix" id="content" data-component="article-container" data-container-type="article"> <main class="c-article-main-column u-float-left js-main-column" data-track-component="article body"> <article lang="en"> <div class="c-article-header"> <header> <ul class="c-article-identifiers" data-test="article-identifier"> <li class="c-article-identifiers__item" data-test="article-category">Short Report</li> <li class="c-article-identifiers__item">Published: <time datetime="2002-10-02">02 October 2002</time></li> </ul> <h1 class="c-article-title" data-test="article-title" data-article-title="">Frequent hypermethylation of the <i>RASSF1A</i> gene in prostate cancer</h1> <ul class="c-article-author-list c-article-author-list--short" data-test="authors-list" data-component-authors-activator="authors-list"><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Limin-Liu-Aff1" data-author-popup="auth-Limin-Liu-Aff1" data-author-search="Liu, Limin">Limin Liu</a><sup class="u-js-hide"><a href="#Aff1">1</a></sup>, </li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Jung_Hoon-Yoon-Aff1" data-author-popup="auth-Jung_Hoon-Yoon-Aff1" data-author-search="Yoon, Jung-Hoon">Jung-Hoon Yoon</a><sup class="u-js-hide"><a href="#Aff1">1</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Reinhard-Dammann-Aff2" data-author-popup="auth-Reinhard-Dammann-Aff2" data-author-search="Dammann, Reinhard">Reinhard Dammann</a><sup class="u-js-hide"><a href="#Aff2">2</a></sup> & </li><li class="c-article-author-list__show-more" aria-label="Show all 4 authors for this article" title="Show all 4 authors for this article">…</li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Gerd_P-Pfeifer-Aff1" data-author-popup="auth-Gerd_P-Pfeifer-Aff1" data-author-search="Pfeifer, Gerd P" data-corresp-id="c1">Gerd P Pfeifer<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-mail-medium"></use></svg></a><sup class="u-js-hide"><a href="#Aff1">1</a></sup> </li></ul><button aria-expanded="false" class="c-article-author-list__button"><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-down-medium"></use></svg><span>Show authors</span></button> <p class="c-article-info-details" data-container-section="info"> <a data-test="journal-link" href="/onc" data-track="click" data-track-action="journal homepage" data-track-category="article body" data-track-label="link"><i data-test="journal-title">Oncogene</i></a> <b data-test="journal-volume"><span class="u-visually-hidden">volume</span> 21</b>, <span class="u-visually-hidden">pages </span>6835–6840 (<span data-test="article-publication-year">2002</span>)<a href="#citeas" class="c-article-info-details__cite-as u-hide-print" data-track="click" data-track-action="cite this article" data-track-label="link">Cite this article</a> </p> <div class="c-article-metrics-bar__wrapper u-clear-both"> <ul class="c-article-metrics-bar u-list-reset"> <li class=" c-article-metrics-bar__item" data-test="access-count"> <p class="c-article-metrics-bar__count">1259 <span class="c-article-metrics-bar__label">Accesses</span></p> </li> <li class="c-article-metrics-bar__item" data-test="altmetric-score"> <p class="c-article-metrics-bar__count">3 <span class="c-article-metrics-bar__label">Altmetric</span></p> </li> <li class="c-article-metrics-bar__item"> <p class="c-article-metrics-bar__details"><a href="/articles/1205814/metrics" data-track="click" data-track-action="view metrics" data-track-label="link" rel="nofollow">Metrics <span class="u-visually-hidden">details</span></a></p> </li> </ul> </div> </header> </div> <div class="c-article-body"> <section aria-labelledby="Abs1" data-title="Abstract" lang="en"><div class="c-article-section" id="Abs1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Abs1">Abstract</h2><div class="c-article-section__content" id="Abs1-content"><p>Recently, we have cloned and characterized the Ras association domain family 1A gene (<i>RASSF1A</i>) at 3p21.3, from which loss of genetic material is one of the most frequent events in several types of human solid tumors. The CpG island promoter region of this gene is highly methylated in several human cancers, most notably in small cell lung cancer, breast cancer, and renal cell carcinoma. In this study, we have analysed the methylation status of <i>RASSF1A</i> in primary prostate tumors and in the prostate cancer cell line LNCaP. In total, 37 out of 52 tumors (71%) were methylated at the promoter region of <i>RASSF1A</i>. The relative frequency of methylation was higher in more aggressive tumors compared with less malignant tumors. For instance, tumors with a Gleason score of 7–10 (25 out of 30, 83%) were significantly more methylated compared with Gleason 4–6 tumors (11 out of 20, 55%, <i>P</i>=0.032, Fisher's exact test). Coincident with a hypermethylated promoter, transcripts of <i>RASSF1A</i> were missing in LNCaP cells. Expression of <i>RASSF1A</i> was restored with 5-aza-2′-deoxycytidine, a DNA methylation inhibitor. In conclusion, our data suggest that epigenetic inactivation of <i>RASSF1A</i> by methylation is a very common event in prostate cancer and might be involved in the progression of the disease. Testing for <i>RASSF1A</i> methylation should become useful in prostate cancer early detection and diagnosis and might aid prognosis by gauging the potential status of progression.</p></div></div></section> <noscript> <div class="c-nature-box c-nature-box--side " data-component="entitlement-box"> <div class="js-access-button"> <a href="https://wayf.springernature.com?redirect_uri=https%3A%2F%2Fwww.nature.com%2Farticles%2F1205814" class="c-article__button" data-test="ra21"> <svg class="u-icon" width="18" height="18" aria-hidden="true" focusable="false"><use href="#icon-institution"></use></svg> <span class="c-article__button-text">Access through your institution</span> </a> </div> <div class="js-buy-button"> <a href="#access-options" class="c-article__button c-article__button--inverted" data-test="ra21"> <span>Buy or subscribe</span> </a> </div> </div> </noscript> <div class="js-context-bar-sticky-point-mobile" data-track-context="article body"> </div> <div 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J. Cancer</i> <b>94</b>: 212–217</p></li></ul><p class="c-article-references__download u-hide-print"><a data-track="click" data-track-action="download citation references" data-track-label="link" rel="nofollow" href="https://citation-needed.springer.com/v2/references/10.1038/sj.onc.1205814?format=refman&flavour=references">Download references<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-download-medium"></use></svg></a></p></div></div></div></section></div><section data-title="Acknowledgements"><div class="c-article-section" id="Ack1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Ack1">Acknowledgements</h2><div class="c-article-section__content" id="Ack1-content"><p>We thank Steven Bates for culturing the LNCaP cells. This study was supported by a grant from the National Institutes of Health (CA88873) to GP Pfeifer.</p></div></div></section><section aria-labelledby="author-information" data-title="Author information"><div class="c-article-section" id="author-information-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="author-information">Author information</h2><div class="c-article-section__content" id="author-information-content"><h3 class="c-article__sub-heading" id="affiliations">Authors and Affiliations</h3><ol class="c-article-author-affiliation__list"><li id="Aff1"><p class="c-article-author-affiliation__address">Department of Biology, Beckman Research Institute, City of Hope Cancer Center, Duarte, 91010, California, CA, USA</p><p class="c-article-author-affiliation__authors-list">Limin Liu, Jung-Hoon Yoon & Gerd P Pfeifer</p></li><li id="Aff2"><p class="c-article-author-affiliation__address">Institut für Humangenetik und Medizinische Biologie, Martin-Luther-Universität Halle-Wittenberg, D-06097 Halle/Saale, Germany</p><p class="c-article-author-affiliation__authors-list">Reinhard Dammann</p></li></ol><div class="u-js-hide u-hide-print" data-test="author-info"><span class="c-article__sub-heading">Authors</span><ol class="c-article-authors-search u-list-reset"><li id="auth-Limin-Liu-Aff1"><span class="c-article-authors-search__title u-h3 js-search-name">Limin Liu</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?author=Limin%20Liu" class="c-article-button" data-track="click" data-track-action="author link - publication" data-track-label="link" rel="nofollow">View author publications</a></div><div class="c-article-authors-search__item c-article-authors-search__list-item--right"><p class="search-in-title-js c-article-authors-search__text">You can also search for this author in <span class="c-article-identifiers"><a 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class="c-article-authors-search__title u-h3 js-search-name">Reinhard Dammann</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?author=Reinhard%20Dammann" class="c-article-button" data-track="click" data-track-action="author link - publication" data-track-label="link" rel="nofollow">View author publications</a></div><div class="c-article-authors-search__item c-article-authors-search__list-item--right"><p class="search-in-title-js c-article-authors-search__text">You can also search for this author in <span class="c-article-identifiers"><a class="c-article-identifiers__item" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=Reinhard%20Dammann" data-track="click" data-track-action="author link - pubmed" data-track-label="link" rel="nofollow">PubMed</a><span class="u-hide"> </span><a class="c-article-identifiers__item" href="http://scholar.google.co.uk/scholar?as_q=&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=%22Reinhard%20Dammann%22&as_publication=&as_ylo=&as_yhi=&as_allsubj=all&hl=en" data-track="click" data-track-action="author link - scholar" data-track-label="link" rel="nofollow">Google Scholar</a></span></p></div></div></li><li id="auth-Gerd_P-Pfeifer-Aff1"><span class="c-article-authors-search__title u-h3 js-search-name">Gerd P Pfeifer</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?author=Gerd%20P%20Pfeifer" class="c-article-button" data-track="click" data-track-action="author link - publication" data-track-label="link" rel="nofollow">View author publications</a></div><div class="c-article-authors-search__item c-article-authors-search__list-item--right"><p class="search-in-title-js c-article-authors-search__text">You can also search for this author in <span class="c-article-identifiers"><a class="c-article-identifiers__item" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=Gerd%20P%20Pfeifer" data-track="click" data-track-action="author link - pubmed" data-track-label="link" rel="nofollow">PubMed</a><span class="u-hide"> </span><a class="c-article-identifiers__item" href="http://scholar.google.co.uk/scholar?as_q=&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=%22Gerd%20P%20Pfeifer%22&as_publication=&as_ylo=&as_yhi=&as_allsubj=all&hl=en" data-track="click" data-track-action="author link - scholar" data-track-label="link" rel="nofollow">Google Scholar</a></span></p></div></div></li></ol></div><h3 class="c-article__sub-heading" id="corresponding-author">Corresponding author</h3><p id="corresponding-author-list">Correspondence to <a id="corresp-c1" href="mailto:gpfeifer@coh.org">Gerd P Pfeifer</a>.</p></div></div></section><section data-title="Rights and permissions"><div class="c-article-section" id="rightslink-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="rightslink">Rights and permissions</h2><div class="c-article-section__content" id="rightslink-content"><p class="c-article-rights"><a data-track="click" data-track-action="view rights and permissions" data-track-label="link" href="https://s100.copyright.com/AppDispatchServlet?title=Frequent%20hypermethylation%20of%20the%20RASSF1A%20gene%20in%20prostate%20cancer&author=Limin%20Liu%20et%20al&contentID=10.1038%2Fsj.onc.1205814&copyright=Macmillan%20Publishers%20Limited&publication=0950-9232&publicationDate=2002-10-02&publisherName=SpringerNature&orderBeanReset=true">Reprints and permissions</a></p></div></div></section><section aria-labelledby="article-info" data-title="About this article"><div class="c-article-section" id="article-info-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="article-info">About this article</h2><div class="c-article-section__content" id="article-info-content"><div class="c-bibliographic-information"><div class="c-bibliographic-information__column"><h3 class="c-article__sub-heading" id="citeas">Cite this article</h3><p class="c-bibliographic-information__citation">Liu, L., Yoon, JH., Dammann, R. <i>et al.</i> Frequent hypermethylation of the <i>RASSF1A</i> gene in prostate cancer. <i>Oncogene</i> <b>21</b>, 6835–6840 (2002). https://doi.org/10.1038/sj.onc.1205814</p><p class="c-bibliographic-information__download-citation u-hide-print"><a data-test="citation-link" data-track="click" data-track-action="download article citation" data-track-label="link" data-track-external="" rel="nofollow" href="https://citation-needed.springer.com/v2/references/10.1038/sj.onc.1205814?format=refman&flavour=citation">Download citation<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-download-medium"></use></svg></a></p><ul class="c-bibliographic-information__list" data-test="publication-history"><li class="c-bibliographic-information__list-item"><p>Received<span class="u-hide">: </span><span class="c-bibliographic-information__value"><time datetime="2002-03-26">26 March 2002</time></span></p></li><li class="c-bibliographic-information__list-item"><p>Revised<span class="u-hide">: </span><span class="c-bibliographic-information__value"><time datetime="2002-06-14">14 June 2002</time></span></p></li><li class="c-bibliographic-information__list-item"><p>Accepted<span class="u-hide">: </span><span class="c-bibliographic-information__value"><time datetime="2002-06-28">28 June 2002</time></span></p></li><li class="c-bibliographic-information__list-item"><p>Published<span class="u-hide">: </span><span class="c-bibliographic-information__value"><time datetime="2002-10-02">02 October 2002</time></span></p></li><li 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Frequent hypermethylation of the RASSF1A gene in prostate cancer | Oncogene