Activin signaling in microsatellite stable colon cancers is disrupted by a combination of genetic and epigenetic mechanisms
Activin receptor 2 (ACVR2) is commonly mutated in microsatellite unstable (MSI) colon cancers, leading to protein loss, signaling disruption, and larger tumors. Here, we examined activin signaling disruption in microsatellite stable (MSS) colon cancers. Fifty-one population-based MSS colon cancers w...
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| Veröffentlicht in: | PloS one 2009-12, Vol.4 (12), p.e8308-e8308 |
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| creator | Jung, Barbara Gomez, Jessica Chau, Eddy Cabral, Jennifer Lee, Jeffrey K Anselm, Aimee Slowik, Przemyslaw Ream-Robinson, Deena Messer, Karen Sporn, Judith Shin, Sung K Boland, C Richard Goel, Ajay Carethers, John M |
| description | Activin receptor 2 (ACVR2) is commonly mutated in microsatellite unstable (MSI) colon cancers, leading to protein loss, signaling disruption, and larger tumors. Here, we examined activin signaling disruption in microsatellite stable (MSS) colon cancers.
Fifty-one population-based MSS colon cancers were assessed for ACVR1, ACVR2 and pSMAD2 protein. Consensus mutation-prone portions of ACVR2 were sequenced in primary cancers and all exons in colon cancer cell lines. Loss of heterozygosity (LOH) was evaluated for ACVR2 and ACVR1, and ACVR2 promoter methylation by methylation-specific PCR and bisulfite sequencing and chromosomal instability (CIN) phenotype via fluorescent LOH analysis of 3 duplicate markers. ACVR2 promoter methylation and ACVR2 expression were assessed in colon cancer cell lines via qPCR and IP-Western blots. Re-expression of ACVR2 after demethylation with 5-aza-2'-deoxycytidine (5-Aza) was determined. An additional 26 MSS colon cancers were assessed for ACVR2 loss and its mechanism, and ACVR2 loss in all tested cancers correlated with clinicopathological criteria.
Of 51 MSS colon tumors, 7 (14%) lost ACVR2, 2 (4%) ACVR1, and 5 (10%) pSMAD2 expression. No somatic ACVR2 mutations were detected. Loss of ACVR2 expression was associated with LOH at ACVR2 (p |
| doi_str_mv | 10.1371/journal.pone.0008308 |
| format | Article |
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Fifty-one population-based MSS colon cancers were assessed for ACVR1, ACVR2 and pSMAD2 protein. Consensus mutation-prone portions of ACVR2 were sequenced in primary cancers and all exons in colon cancer cell lines. Loss of heterozygosity (LOH) was evaluated for ACVR2 and ACVR1, and ACVR2 promoter methylation by methylation-specific PCR and bisulfite sequencing and chromosomal instability (CIN) phenotype via fluorescent LOH analysis of 3 duplicate markers. ACVR2 promoter methylation and ACVR2 expression were assessed in colon cancer cell lines via qPCR and IP-Western blots. Re-expression of ACVR2 after demethylation with 5-aza-2'-deoxycytidine (5-Aza) was determined. An additional 26 MSS colon cancers were assessed for ACVR2 loss and its mechanism, and ACVR2 loss in all tested cancers correlated with clinicopathological criteria.
Of 51 MSS colon tumors, 7 (14%) lost ACVR2, 2 (4%) ACVR1, and 5 (10%) pSMAD2 expression. No somatic ACVR2 mutations were detected. Loss of ACVR2 expression was associated with LOH at ACVR2 (p<0.001) and ACVR2 promoter hypermethylation (p<0.05). ACVR2 LOH, but not promoter hypermethylation, correlated with CIN status. In colon cancer cell lines with fully methylated ACVR2 promoter, loss of ACVR2 mRNA and protein expression was restored with 5-Aza treatment. Loss of ACVR2 was associated with an increase in primary colon cancer volume (p<0.05).
Only a small percentage of MSS colon cancers lose expression of activin signaling members. ACVR2 loss occurs through LOH and ACVR2 promoter hypermethylation, revealing distinct mechanisms for ACVR2 inactivation in both MSI and MSS subtypes of colon cancer.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0008308</identifier><identifier>PMID: 20011542</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Activin ; activin receptors ; Activin Receptors, Type I - genetics ; Activin Receptors, Type II - genetics ; Analysis ; Biotechnology ; Bisulfite ; Cancer ; Cancer genetics ; Cell Line, Tumor ; Colon ; Colon cancer ; Colonic Neoplasms - classification ; Colonic Neoplasms - genetics ; Colorectal cancer ; Deactivation ; Demethylation ; Disruption ; DNA methylation ; DNA Methylation - genetics ; Epigenesis, Genetic ; Epigenetic inheritance ; Epigenetics ; Exons ; Fluorescence ; Gastroenterology ; Gastroenterology and Hepatology/Colon and Rectum ; Gastroenterology and Hepatology/Gastrointestinal Cancers ; Gastrointestinal diseases ; Gene expression ; Gene Expression Regulation, Neoplastic ; Genetics and Genomics/Cancer Genetics ; Genetics and Genomics/Epigenetics ; Genomic instability ; Growth factors ; Heterozygosity ; Humans ; Inactivation ; Kinases ; Loss of heterozygosity ; Loss of Heterozygosity - genetics ; Medicine ; Methylation ; Microsatellite Instability ; Microsatellite Repeats - genetics ; Microsatellites ; mRNA ; Mutation ; Mutation - genetics ; Polymerase chain reaction ; Promoter Regions, Genetic - genetics ; Promoters ; Protein expression ; Proteins ; Signal transduction ; Signal Transduction - genetics ; Signaling ; Smad2 Protein - genetics ; Stability ; Stability analysis ; Sulfites ; Transcription, Genetic ; Tumor Burden - genetics ; Tumor cell lines ; Tumors ; Western blotting</subject><ispartof>PloS one, 2009-12, Vol.4 (12), p.e8308-e8308</ispartof><rights>COPYRIGHT 2009 Public Library of Science</rights><rights>This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. 2009</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c792t-9d3dc8102e34a5b7d811ed6a0288f6ded8bcfab6106cbf4b921f004cb9eab88c3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2789408/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2789408/$$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/20011542$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Jung, Barbara</creatorcontrib><creatorcontrib>Gomez, Jessica</creatorcontrib><creatorcontrib>Chau, Eddy</creatorcontrib><creatorcontrib>Cabral, Jennifer</creatorcontrib><creatorcontrib>Lee, Jeffrey K</creatorcontrib><creatorcontrib>Anselm, Aimee</creatorcontrib><creatorcontrib>Slowik, Przemyslaw</creatorcontrib><creatorcontrib>Ream-Robinson, Deena</creatorcontrib><creatorcontrib>Messer, Karen</creatorcontrib><creatorcontrib>Sporn, Judith</creatorcontrib><creatorcontrib>Shin, Sung K</creatorcontrib><creatorcontrib>Boland, C Richard</creatorcontrib><creatorcontrib>Goel, Ajay</creatorcontrib><creatorcontrib>Carethers, John M</creatorcontrib><title>Activin signaling in microsatellite stable colon cancers is disrupted by a combination of genetic and epigenetic mechanisms</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Activin receptor 2 (ACVR2) is commonly mutated in microsatellite unstable (MSI) colon cancers, leading to protein loss, signaling disruption, and larger tumors. Here, we examined activin signaling disruption in microsatellite stable (MSS) colon cancers.
Fifty-one population-based MSS colon cancers were assessed for ACVR1, ACVR2 and pSMAD2 protein. Consensus mutation-prone portions of ACVR2 were sequenced in primary cancers and all exons in colon cancer cell lines. Loss of heterozygosity (LOH) was evaluated for ACVR2 and ACVR1, and ACVR2 promoter methylation by methylation-specific PCR and bisulfite sequencing and chromosomal instability (CIN) phenotype via fluorescent LOH analysis of 3 duplicate markers. ACVR2 promoter methylation and ACVR2 expression were assessed in colon cancer cell lines via qPCR and IP-Western blots. Re-expression of ACVR2 after demethylation with 5-aza-2'-deoxycytidine (5-Aza) was determined. An additional 26 MSS colon cancers were assessed for ACVR2 loss and its mechanism, and ACVR2 loss in all tested cancers correlated with clinicopathological criteria.
Of 51 MSS colon tumors, 7 (14%) lost ACVR2, 2 (4%) ACVR1, and 5 (10%) pSMAD2 expression. No somatic ACVR2 mutations were detected. Loss of ACVR2 expression was associated with LOH at ACVR2 (p<0.001) and ACVR2 promoter hypermethylation (p<0.05). ACVR2 LOH, but not promoter hypermethylation, correlated with CIN status. In colon cancer cell lines with fully methylated ACVR2 promoter, loss of ACVR2 mRNA and protein expression was restored with 5-Aza treatment. Loss of ACVR2 was associated with an increase in primary colon cancer volume (p<0.05).
Only a small percentage of MSS colon cancers lose expression of activin signaling members. ACVR2 loss occurs through LOH and ACVR2 promoter hypermethylation, revealing distinct mechanisms for ACVR2 inactivation in both MSI and MSS subtypes of colon cancer.</description><subject>Activin</subject><subject>activin receptors</subject><subject>Activin Receptors, Type I - genetics</subject><subject>Activin Receptors, Type II - genetics</subject><subject>Analysis</subject><subject>Biotechnology</subject><subject>Bisulfite</subject><subject>Cancer</subject><subject>Cancer genetics</subject><subject>Cell Line, Tumor</subject><subject>Colon</subject><subject>Colon cancer</subject><subject>Colonic Neoplasms - classification</subject><subject>Colonic Neoplasms - genetics</subject><subject>Colorectal cancer</subject><subject>Deactivation</subject><subject>Demethylation</subject><subject>Disruption</subject><subject>DNA methylation</subject><subject>DNA Methylation - genetics</subject><subject>Epigenesis, Genetic</subject><subject>Epigenetic inheritance</subject><subject>Epigenetics</subject><subject>Exons</subject><subject>Fluorescence</subject><subject>Gastroenterology</subject><subject>Gastroenterology and Hepatology/Colon and Rectum</subject><subject>Gastroenterology and Hepatology/Gastrointestinal Cancers</subject><subject>Gastrointestinal diseases</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Genetics and Genomics/Cancer Genetics</subject><subject>Genetics and Genomics/Epigenetics</subject><subject>Genomic instability</subject><subject>Growth factors</subject><subject>Heterozygosity</subject><subject>Humans</subject><subject>Inactivation</subject><subject>Kinases</subject><subject>Loss of heterozygosity</subject><subject>Loss of Heterozygosity - genetics</subject><subject>Medicine</subject><subject>Methylation</subject><subject>Microsatellite Instability</subject><subject>Microsatellite Repeats - genetics</subject><subject>Microsatellites</subject><subject>mRNA</subject><subject>Mutation</subject><subject>Mutation - genetics</subject><subject>Polymerase chain reaction</subject><subject>Promoter Regions, Genetic - genetics</subject><subject>Promoters</subject><subject>Protein expression</subject><subject>Proteins</subject><subject>Signal transduction</subject><subject>Signal Transduction - genetics</subject><subject>Signaling</subject><subject>Smad2 Protein - genetics</subject><subject>Stability</subject><subject>Stability analysis</subject><subject>Sulfites</subject><subject>Transcription, Genetic</subject><subject>Tumor Burden - genetics</subject><subject>Tumor cell lines</subject><subject>Tumors</subject><subject>Western blotting</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk1uLEzEUxwdR3HX1G4gOCCs-tOY2k8yLUBYvCwsL3l5DbjNNmUnqJLO4-OU9te3SiqjJQ26_809yLkXxFKM5phy_XsVpDKqfr2Nwc4SQoEjcK05xQ8msJojeP5ifFI9SWiFUUVHXD4sTghDGFSOnxY-Fyf7GhzL5DtR86EpYDN6MMans-t5nV6asdO9KE_sYSqOCcWMqfSqtT-O0zs6W-rZUcD5oH1T2QMW27Fxw2ZtSBVu6td8vB2eWKvg0pMfFg1b1yT3ZjWfFl3dvP198mF1dv7-8WFzNDG9InjWWWiMwIo4yVWluBcbO1goRIdraOiu0aZWuMaqNbpluCG4RYkY3TmkhDD0rnm91131Mcue3JDFpsGhqLBgQl1vCRrWS69EParyVUXn5ayOOnVQjPL53EmvDbFXRVtCW2RpruAlEKgxDY7gFrTe72yY9OGtcyKPqj0SPT4Jfyi7eSMJFwyCMZ8XLncAYv00uZTn4ZCAUKrg4JclZ1SCGKPs3SSmGxjmQ538lCWZMcE4AfPEb-Gd_zbdUp8AlPrQRfmKgWwepAwnZethfME44RxRhMHh1ZABMdt9zp6aU5OWnj__PXn89Zs8P2KVTfV6m2E-bHEzHINuCm8ROo2vvAoKR3NTT_p9yU09yV09g9uwwmHdG-wKiPwExeh1t</recordid><startdate>20091214</startdate><enddate>20091214</enddate><creator>Jung, Barbara</creator><creator>Gomez, Jessica</creator><creator>Chau, Eddy</creator><creator>Cabral, Jennifer</creator><creator>Lee, Jeffrey K</creator><creator>Anselm, Aimee</creator><creator>Slowik, Przemyslaw</creator><creator>Ream-Robinson, Deena</creator><creator>Messer, Karen</creator><creator>Sporn, Judith</creator><creator>Shin, Sung K</creator><creator>Boland, C Richard</creator><creator>Goel, Ajay</creator><creator>Carethers, John M</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>20091214</creationdate><title>Activin signaling in microsatellite stable colon cancers is disrupted by a combination of genetic and epigenetic mechanisms</title><author>Jung, Barbara ; Gomez, Jessica ; Chau, Eddy ; Cabral, Jennifer ; Lee, Jeffrey K ; Anselm, Aimee ; Slowik, Przemyslaw ; Ream-Robinson, Deena ; Messer, Karen ; Sporn, Judith ; Shin, Sung K ; Boland, C Richard ; Goel, Ajay ; Carethers, John M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c792t-9d3dc8102e34a5b7d811ed6a0288f6ded8bcfab6106cbf4b921f004cb9eab88c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Activin</topic><topic>activin receptors</topic><topic>Activin Receptors, Type I - genetics</topic><topic>Activin Receptors, Type II - genetics</topic><topic>Analysis</topic><topic>Biotechnology</topic><topic>Bisulfite</topic><topic>Cancer</topic><topic>Cancer genetics</topic><topic>Cell Line, Tumor</topic><topic>Colon</topic><topic>Colon cancer</topic><topic>Colonic Neoplasms - classification</topic><topic>Colonic Neoplasms - genetics</topic><topic>Colorectal cancer</topic><topic>Deactivation</topic><topic>Demethylation</topic><topic>Disruption</topic><topic>DNA methylation</topic><topic>DNA Methylation - genetics</topic><topic>Epigenesis, Genetic</topic><topic>Epigenetic inheritance</topic><topic>Epigenetics</topic><topic>Exons</topic><topic>Fluorescence</topic><topic>Gastroenterology</topic><topic>Gastroenterology and Hepatology/Colon and Rectum</topic><topic>Gastroenterology and Hepatology/Gastrointestinal Cancers</topic><topic>Gastrointestinal diseases</topic><topic>Gene expression</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Genetics and Genomics/Cancer Genetics</topic><topic>Genetics and Genomics/Epigenetics</topic><topic>Genomic instability</topic><topic>Growth factors</topic><topic>Heterozygosity</topic><topic>Humans</topic><topic>Inactivation</topic><topic>Kinases</topic><topic>Loss of heterozygosity</topic><topic>Loss of Heterozygosity - genetics</topic><topic>Medicine</topic><topic>Methylation</topic><topic>Microsatellite Instability</topic><topic>Microsatellite Repeats - genetics</topic><topic>Microsatellites</topic><topic>mRNA</topic><topic>Mutation</topic><topic>Mutation - genetics</topic><topic>Polymerase chain reaction</topic><topic>Promoter Regions, Genetic - genetics</topic><topic>Promoters</topic><topic>Protein expression</topic><topic>Proteins</topic><topic>Signal transduction</topic><topic>Signal Transduction - genetics</topic><topic>Signaling</topic><topic>Smad2 Protein - genetics</topic><topic>Stability</topic><topic>Stability analysis</topic><topic>Sulfites</topic><topic>Transcription, Genetic</topic><topic>Tumor Burden - genetics</topic><topic>Tumor cell lines</topic><topic>Tumors</topic><topic>Western blotting</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jung, Barbara</creatorcontrib><creatorcontrib>Gomez, Jessica</creatorcontrib><creatorcontrib>Chau, Eddy</creatorcontrib><creatorcontrib>Cabral, Jennifer</creatorcontrib><creatorcontrib>Lee, Jeffrey K</creatorcontrib><creatorcontrib>Anselm, Aimee</creatorcontrib><creatorcontrib>Slowik, Przemyslaw</creatorcontrib><creatorcontrib>Ream-Robinson, Deena</creatorcontrib><creatorcontrib>Messer, Karen</creatorcontrib><creatorcontrib>Sporn, Judith</creatorcontrib><creatorcontrib>Shin, Sung K</creatorcontrib><creatorcontrib>Boland, C Richard</creatorcontrib><creatorcontrib>Goel, Ajay</creatorcontrib><creatorcontrib>Carethers, John M</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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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>Jung, Barbara</au><au>Gomez, Jessica</au><au>Chau, Eddy</au><au>Cabral, Jennifer</au><au>Lee, Jeffrey K</au><au>Anselm, Aimee</au><au>Slowik, Przemyslaw</au><au>Ream-Robinson, Deena</au><au>Messer, Karen</au><au>Sporn, Judith</au><au>Shin, Sung K</au><au>Boland, C Richard</au><au>Goel, Ajay</au><au>Carethers, John M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Activin signaling in microsatellite stable colon cancers is disrupted by a combination of genetic and epigenetic mechanisms</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2009-12-14</date><risdate>2009</risdate><volume>4</volume><issue>12</issue><spage>e8308</spage><epage>e8308</epage><pages>e8308-e8308</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Activin receptor 2 (ACVR2) is commonly mutated in microsatellite unstable (MSI) colon cancers, leading to protein loss, signaling disruption, and larger tumors. Here, we examined activin signaling disruption in microsatellite stable (MSS) colon cancers.
Fifty-one population-based MSS colon cancers were assessed for ACVR1, ACVR2 and pSMAD2 protein. Consensus mutation-prone portions of ACVR2 were sequenced in primary cancers and all exons in colon cancer cell lines. Loss of heterozygosity (LOH) was evaluated for ACVR2 and ACVR1, and ACVR2 promoter methylation by methylation-specific PCR and bisulfite sequencing and chromosomal instability (CIN) phenotype via fluorescent LOH analysis of 3 duplicate markers. ACVR2 promoter methylation and ACVR2 expression were assessed in colon cancer cell lines via qPCR and IP-Western blots. Re-expression of ACVR2 after demethylation with 5-aza-2'-deoxycytidine (5-Aza) was determined. An additional 26 MSS colon cancers were assessed for ACVR2 loss and its mechanism, and ACVR2 loss in all tested cancers correlated with clinicopathological criteria.
Of 51 MSS colon tumors, 7 (14%) lost ACVR2, 2 (4%) ACVR1, and 5 (10%) pSMAD2 expression. No somatic ACVR2 mutations were detected. Loss of ACVR2 expression was associated with LOH at ACVR2 (p<0.001) and ACVR2 promoter hypermethylation (p<0.05). ACVR2 LOH, but not promoter hypermethylation, correlated with CIN status. In colon cancer cell lines with fully methylated ACVR2 promoter, loss of ACVR2 mRNA and protein expression was restored with 5-Aza treatment. Loss of ACVR2 was associated with an increase in primary colon cancer volume (p<0.05).
Only a small percentage of MSS colon cancers lose expression of activin signaling members. ACVR2 loss occurs through LOH and ACVR2 promoter hypermethylation, revealing distinct mechanisms for ACVR2 inactivation in both MSI and MSS subtypes of colon cancer.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>20011542</pmid><doi>10.1371/journal.pone.0008308</doi><tpages>e8308</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2009-12, Vol.4 (12), p.e8308-e8308 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1291896184 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Activin activin receptors Activin Receptors, Type I - genetics Activin Receptors, Type II - genetics Analysis Biotechnology Bisulfite Cancer Cancer genetics Cell Line, Tumor Colon Colon cancer Colonic Neoplasms - classification Colonic Neoplasms - genetics Colorectal cancer Deactivation Demethylation Disruption DNA methylation DNA Methylation - genetics Epigenesis, Genetic Epigenetic inheritance Epigenetics Exons Fluorescence Gastroenterology Gastroenterology and Hepatology/Colon and Rectum Gastroenterology and Hepatology/Gastrointestinal Cancers Gastrointestinal diseases Gene expression Gene Expression Regulation, Neoplastic Genetics and Genomics/Cancer Genetics Genetics and Genomics/Epigenetics Genomic instability Growth factors Heterozygosity Humans Inactivation Kinases Loss of heterozygosity Loss of Heterozygosity - genetics Medicine Methylation Microsatellite Instability Microsatellite Repeats - genetics Microsatellites mRNA Mutation Mutation - genetics Polymerase chain reaction Promoter Regions, Genetic - genetics Promoters Protein expression Proteins Signal transduction Signal Transduction - genetics Signaling Smad2 Protein - genetics Stability Stability analysis Sulfites Transcription, Genetic Tumor Burden - genetics Tumor cell lines Tumors Western blotting |
| title | Activin signaling in microsatellite stable colon cancers is disrupted by a combination of genetic and epigenetic mechanisms |
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