Epigenome-wide association study in hepatocellular carcinoma: Identification of stochastic epigenetic mutations through an innovative statistical approach
Hepatocellular carcinoma (HCC) results from accumulation of both genetic and epigenetic alterations. We investigated the genome-wide DNA methylation profile in 69 pairs of HCC and adjacent non-cancerous liver tissues using the Infinium HumanMethylation 450K BeadChip array. An innovative analytical a...
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| Veröffentlicht in: | Oncotarget 2017-06, Vol.8 (26), p.41890-41902 |
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| creator | Gentilini, Davide Scala, Stefania Gaudenzi, Germano Garagnani, Paolo Capri, Miriam Cescon, Matteo Grazi, Gian Luca Bacalini, Maria Giulia Pisoni, Serena Dicitore, Alessandra Circelli, Luisa Santagata, Sara Izzo, Francesco Di Blasio, Anna Maria Persani, Luca Franceschi, Claudio Vitale, Giovanni |
| description | Hepatocellular carcinoma (HCC) results from accumulation of both genetic and epigenetic alterations. We investigated the genome-wide DNA methylation profile in 69 pairs of HCC and adjacent non-cancerous liver tissues using the Infinium HumanMethylation 450K BeadChip array. An innovative analytical approach has been adopted to identify Stochastic Epigenetic Mutations (SEMs) in HCC.HCC and peritumoral tissues showed a different epigenetic profile, mainly characterized by loss of DNA methylation in HCC. Total number of SEMs was significantly higher in HCC tumor (median: 77,370) than in peritumoral (median: 5,656) tissues and correlated with tumor grade. A significant positive association emerged between SEMs measured in peritumoral tissue and hepatitis B and/or C virus infection status. A restricted number of SEMs resulted to be shared by more than 90% of HCC tumor samples and never present in peritumoral tissue. This analysis allowed the identification of four epigenetically regulated candidate genes (AJAP1, ADARB2, PTPRN2, SDK1), potentially involved in the pathogenesis of HCC.In conclusion, HCC showed a methylation profile completely deregulated and very far from adjacent non-cancerous liver tissues. The SEM analysis provided valuable clues for further investigations in understanding the process of tumorigenesis in HCC. |
| doi_str_mv | 10.18632/oncotarget.17462 |
| format | Article |
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We investigated the genome-wide DNA methylation profile in 69 pairs of HCC and adjacent non-cancerous liver tissues using the Infinium HumanMethylation 450K BeadChip array. An innovative analytical approach has been adopted to identify Stochastic Epigenetic Mutations (SEMs) in HCC.HCC and peritumoral tissues showed a different epigenetic profile, mainly characterized by loss of DNA methylation in HCC. Total number of SEMs was significantly higher in HCC tumor (median: 77,370) than in peritumoral (median: 5,656) tissues and correlated with tumor grade. A significant positive association emerged between SEMs measured in peritumoral tissue and hepatitis B and/or C virus infection status. A restricted number of SEMs resulted to be shared by more than 90% of HCC tumor samples and never present in peritumoral tissue. This analysis allowed the identification of four epigenetically regulated candidate genes (AJAP1, ADARB2, PTPRN2, SDK1), potentially involved in the pathogenesis of HCC.In conclusion, HCC showed a methylation profile completely deregulated and very far from adjacent non-cancerous liver tissues. The SEM analysis provided valuable clues for further investigations in understanding the process of tumorigenesis in HCC.</description><identifier>ISSN: 1949-2553</identifier><identifier>EISSN: 1949-2553</identifier><identifier>DOI: 10.18632/oncotarget.17462</identifier><identifier>PMID: 28514750</identifier><language>eng</language><publisher>United States: Impact Journals LLC</publisher><subject>Adult ; Aged ; Biomarkers, Tumor ; Carcinogenesis - genetics ; Carcinoma, Hepatocellular - etiology ; Carcinoma, Hepatocellular - genetics ; Carcinoma, Hepatocellular - pathology ; Cluster Analysis ; Computational Biology ; DNA Methylation ; Epigenesis, Genetic ; Epigenomics - methods ; Female ; Gene Expression Profiling ; Genetic Predisposition to Disease ; Genome-Wide Association Study - methods ; Humans ; Liver Neoplasms - etiology ; Liver Neoplasms - genetics ; Liver Neoplasms - pathology ; Male ; Middle Aged ; Molecular Sequence Annotation ; Mutation ; Neoplasm Grading ; Research Paper ; Tumor Burden</subject><ispartof>Oncotarget, 2017-06, Vol.8 (26), p.41890-41902</ispartof><rights>Copyright: © 2017 Gentilini et al. 2017</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c465t-c9e978bcefc8b26c3b851c26c4ece176f9e58b5075d0fb0545c0935097a307623</citedby><cites>FETCH-LOGICAL-c465t-c9e978bcefc8b26c3b851c26c4ece176f9e58b5075d0fb0545c0935097a307623</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/PMC5522036/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5522036/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28514750$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gentilini, Davide</creatorcontrib><creatorcontrib>Scala, Stefania</creatorcontrib><creatorcontrib>Gaudenzi, Germano</creatorcontrib><creatorcontrib>Garagnani, Paolo</creatorcontrib><creatorcontrib>Capri, Miriam</creatorcontrib><creatorcontrib>Cescon, Matteo</creatorcontrib><creatorcontrib>Grazi, Gian Luca</creatorcontrib><creatorcontrib>Bacalini, Maria Giulia</creatorcontrib><creatorcontrib>Pisoni, Serena</creatorcontrib><creatorcontrib>Dicitore, Alessandra</creatorcontrib><creatorcontrib>Circelli, Luisa</creatorcontrib><creatorcontrib>Santagata, Sara</creatorcontrib><creatorcontrib>Izzo, Francesco</creatorcontrib><creatorcontrib>Di Blasio, Anna Maria</creatorcontrib><creatorcontrib>Persani, Luca</creatorcontrib><creatorcontrib>Franceschi, Claudio</creatorcontrib><creatorcontrib>Vitale, Giovanni</creatorcontrib><title>Epigenome-wide association study in hepatocellular carcinoma: Identification of stochastic epigenetic mutations through an innovative statistical approach</title><title>Oncotarget</title><addtitle>Oncotarget</addtitle><description>Hepatocellular carcinoma (HCC) results from accumulation of both genetic and epigenetic alterations. We investigated the genome-wide DNA methylation profile in 69 pairs of HCC and adjacent non-cancerous liver tissues using the Infinium HumanMethylation 450K BeadChip array. An innovative analytical approach has been adopted to identify Stochastic Epigenetic Mutations (SEMs) in HCC.HCC and peritumoral tissues showed a different epigenetic profile, mainly characterized by loss of DNA methylation in HCC. Total number of SEMs was significantly higher in HCC tumor (median: 77,370) than in peritumoral (median: 5,656) tissues and correlated with tumor grade. A significant positive association emerged between SEMs measured in peritumoral tissue and hepatitis B and/or C virus infection status. A restricted number of SEMs resulted to be shared by more than 90% of HCC tumor samples and never present in peritumoral tissue. This analysis allowed the identification of four epigenetically regulated candidate genes (AJAP1, ADARB2, PTPRN2, SDK1), potentially involved in the pathogenesis of HCC.In conclusion, HCC showed a methylation profile completely deregulated and very far from adjacent non-cancerous liver tissues. The SEM analysis provided valuable clues for further investigations in understanding the process of tumorigenesis in HCC.</description><subject>Adult</subject><subject>Aged</subject><subject>Biomarkers, Tumor</subject><subject>Carcinogenesis - genetics</subject><subject>Carcinoma, Hepatocellular - etiology</subject><subject>Carcinoma, Hepatocellular - genetics</subject><subject>Carcinoma, Hepatocellular - pathology</subject><subject>Cluster Analysis</subject><subject>Computational Biology</subject><subject>DNA Methylation</subject><subject>Epigenesis, Genetic</subject><subject>Epigenomics - methods</subject><subject>Female</subject><subject>Gene Expression Profiling</subject><subject>Genetic Predisposition to Disease</subject><subject>Genome-Wide Association Study - methods</subject><subject>Humans</subject><subject>Liver Neoplasms - etiology</subject><subject>Liver Neoplasms - genetics</subject><subject>Liver Neoplasms - pathology</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Molecular Sequence Annotation</subject><subject>Mutation</subject><subject>Neoplasm Grading</subject><subject>Research Paper</subject><subject>Tumor Burden</subject><issn>1949-2553</issn><issn>1949-2553</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkc9u1DAQxi0EolXpA3BBPnJJ8Z84iTkgoapApUpc4Gw5k8nGKLGD7Szqq_C0eHdLKb7MyJ7fN575CHnN2RXvGineBQ8h27jDfMXbuhHPyDnXta6EUvL5k_yMXKb0g5Wj6rYT-iU5E53idavYOfl9s7od-rBg9csNSG1KAZzNLnia8jbcU-fphKvNAXCet9lGCjaCK4h9T28H9NmNDk5EGAsUYLIpO6B4lMZDumz5WJFonmLYdhO1vij7sC_XeyxUiQfIztSuawwWplfkxWjnhJcP8YJ8_3Tz7fpLdff18-31x7sK6kblCjTqtusBR-h60YDsy3BQkhoBeduMGlXXK9aqgY192YECpqViurWStY2QF-TDSXfd-gUHKBNFO5s1usXGexOsM_-_eDeZXdgbpYRgsikCbx8EYvi5YcpmcemwLesxbMlwzRgXvJa6lPJTKcSQUsTxsQ1n5mir-WerOdpamDdP__dI_DVR_gGkM6d4</recordid><startdate>20170627</startdate><enddate>20170627</enddate><creator>Gentilini, Davide</creator><creator>Scala, Stefania</creator><creator>Gaudenzi, Germano</creator><creator>Garagnani, Paolo</creator><creator>Capri, Miriam</creator><creator>Cescon, Matteo</creator><creator>Grazi, Gian Luca</creator><creator>Bacalini, Maria Giulia</creator><creator>Pisoni, Serena</creator><creator>Dicitore, Alessandra</creator><creator>Circelli, Luisa</creator><creator>Santagata, Sara</creator><creator>Izzo, Francesco</creator><creator>Di Blasio, Anna Maria</creator><creator>Persani, Luca</creator><creator>Franceschi, Claudio</creator><creator>Vitale, Giovanni</creator><general>Impact Journals LLC</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20170627</creationdate><title>Epigenome-wide association study in hepatocellular carcinoma: Identification of stochastic epigenetic mutations through an innovative statistical approach</title><author>Gentilini, Davide ; Scala, Stefania ; Gaudenzi, Germano ; Garagnani, Paolo ; Capri, Miriam ; Cescon, Matteo ; Grazi, Gian Luca ; Bacalini, Maria Giulia ; Pisoni, Serena ; Dicitore, Alessandra ; Circelli, Luisa ; Santagata, Sara ; Izzo, Francesco ; Di Blasio, Anna Maria ; Persani, Luca ; Franceschi, Claudio ; Vitale, Giovanni</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c465t-c9e978bcefc8b26c3b851c26c4ece176f9e58b5075d0fb0545c0935097a307623</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Biomarkers, Tumor</topic><topic>Carcinogenesis - genetics</topic><topic>Carcinoma, Hepatocellular - etiology</topic><topic>Carcinoma, Hepatocellular - genetics</topic><topic>Carcinoma, Hepatocellular - pathology</topic><topic>Cluster Analysis</topic><topic>Computational Biology</topic><topic>DNA Methylation</topic><topic>Epigenesis, Genetic</topic><topic>Epigenomics - methods</topic><topic>Female</topic><topic>Gene Expression Profiling</topic><topic>Genetic Predisposition to Disease</topic><topic>Genome-Wide Association Study - methods</topic><topic>Humans</topic><topic>Liver Neoplasms - etiology</topic><topic>Liver Neoplasms - genetics</topic><topic>Liver Neoplasms - pathology</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Molecular Sequence Annotation</topic><topic>Mutation</topic><topic>Neoplasm Grading</topic><topic>Research Paper</topic><topic>Tumor Burden</topic><toplevel>online_resources</toplevel><creatorcontrib>Gentilini, Davide</creatorcontrib><creatorcontrib>Scala, Stefania</creatorcontrib><creatorcontrib>Gaudenzi, Germano</creatorcontrib><creatorcontrib>Garagnani, Paolo</creatorcontrib><creatorcontrib>Capri, Miriam</creatorcontrib><creatorcontrib>Cescon, Matteo</creatorcontrib><creatorcontrib>Grazi, Gian Luca</creatorcontrib><creatorcontrib>Bacalini, Maria Giulia</creatorcontrib><creatorcontrib>Pisoni, Serena</creatorcontrib><creatorcontrib>Dicitore, Alessandra</creatorcontrib><creatorcontrib>Circelli, Luisa</creatorcontrib><creatorcontrib>Santagata, Sara</creatorcontrib><creatorcontrib>Izzo, Francesco</creatorcontrib><creatorcontrib>Di Blasio, Anna Maria</creatorcontrib><creatorcontrib>Persani, Luca</creatorcontrib><creatorcontrib>Franceschi, Claudio</creatorcontrib><creatorcontrib>Vitale, Giovanni</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Oncotarget</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gentilini, Davide</au><au>Scala, Stefania</au><au>Gaudenzi, Germano</au><au>Garagnani, Paolo</au><au>Capri, Miriam</au><au>Cescon, Matteo</au><au>Grazi, Gian Luca</au><au>Bacalini, Maria Giulia</au><au>Pisoni, Serena</au><au>Dicitore, Alessandra</au><au>Circelli, Luisa</au><au>Santagata, Sara</au><au>Izzo, Francesco</au><au>Di Blasio, Anna Maria</au><au>Persani, Luca</au><au>Franceschi, Claudio</au><au>Vitale, Giovanni</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Epigenome-wide association study in hepatocellular carcinoma: Identification of stochastic epigenetic mutations through an innovative statistical approach</atitle><jtitle>Oncotarget</jtitle><addtitle>Oncotarget</addtitle><date>2017-06-27</date><risdate>2017</risdate><volume>8</volume><issue>26</issue><spage>41890</spage><epage>41902</epage><pages>41890-41902</pages><issn>1949-2553</issn><eissn>1949-2553</eissn><abstract>Hepatocellular carcinoma (HCC) results from accumulation of both genetic and epigenetic alterations. We investigated the genome-wide DNA methylation profile in 69 pairs of HCC and adjacent non-cancerous liver tissues using the Infinium HumanMethylation 450K BeadChip array. An innovative analytical approach has been adopted to identify Stochastic Epigenetic Mutations (SEMs) in HCC.HCC and peritumoral tissues showed a different epigenetic profile, mainly characterized by loss of DNA methylation in HCC. Total number of SEMs was significantly higher in HCC tumor (median: 77,370) than in peritumoral (median: 5,656) tissues and correlated with tumor grade. A significant positive association emerged between SEMs measured in peritumoral tissue and hepatitis B and/or C virus infection status. A restricted number of SEMs resulted to be shared by more than 90% of HCC tumor samples and never present in peritumoral tissue. This analysis allowed the identification of four epigenetically regulated candidate genes (AJAP1, ADARB2, PTPRN2, SDK1), potentially involved in the pathogenesis of HCC.In conclusion, HCC showed a methylation profile completely deregulated and very far from adjacent non-cancerous liver tissues. The SEM analysis provided valuable clues for further investigations in understanding the process of tumorigenesis in HCC.</abstract><cop>United States</cop><pub>Impact Journals LLC</pub><pmid>28514750</pmid><doi>10.18632/oncotarget.17462</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adult Aged Biomarkers, Tumor Carcinogenesis - genetics Carcinoma, Hepatocellular - etiology Carcinoma, Hepatocellular - genetics Carcinoma, Hepatocellular - pathology Cluster Analysis Computational Biology DNA Methylation Epigenesis, Genetic Epigenomics - methods Female Gene Expression Profiling Genetic Predisposition to Disease Genome-Wide Association Study - methods Humans Liver Neoplasms - etiology Liver Neoplasms - genetics Liver Neoplasms - pathology Male Middle Aged Molecular Sequence Annotation Mutation Neoplasm Grading Research Paper Tumor Burden |
| title | Epigenome-wide association study in hepatocellular carcinoma: Identification of stochastic epigenetic mutations through an innovative statistical approach |
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