Mutational analysis of the APC/β-catenin/tcf pathway in colorectal cancer
Mutation of the adenomatous polyposis coli (APC) tumor suppressor gene initiates the majority of colorectal (CR) cancers. One consequence of this inactivation is constitutive activation of beta-catenin/Tcf-mediated transcription. To further explore the role of the APC/beta-catenin/Tcf pathway in CR...
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Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 1998-03, Vol.58 (6), p.1130-1134 |
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description | Mutation of the adenomatous polyposis coli (APC) tumor suppressor gene initiates the majority of colorectal (CR) cancers. One consequence of this inactivation is constitutive activation of beta-catenin/Tcf-mediated transcription. To further explore the role of the APC/beta-catenin/Tcf pathway in CR tumorigenesis, we searched for mutations in genes implicated in this pathway in CR tumors lacking APC mutations. No mutations of the gamma-catenin (CTNNG1), GSK-3alpha (GSK3A), or GSK-3beta (GSK3B) genes were detected. In contrast, mutations in the NH2-terminal regulatory domain of beta-catenin (CTNNB1) were found in 13 of 27 (48%) CR tumors lacking APC mutations. Mutations in the beta-catenin regulatory domain and APC were observed to be mutually exclusive, consistent with their equivalent effects on beta-catenin stability and Tcf transactivation. In addition, we found that CTNNB1 mutations can occur in the early, adenomatous stage of CR neoplasia, as has been observed previously with APC mutations. These results suggest that CTNNB1 mutations can uniquely substitute for APC mutations in CR tumors and that beta-catenin signaling plays a critical role in CR tumorigenesis. |
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B ; MORIN, P. J ; VOGELSTEIN, B ; KINZLER, K. W</creator><creatorcontrib>SPARKS, A. B ; MORIN, P. J ; VOGELSTEIN, B ; KINZLER, K. W</creatorcontrib><description>Mutation of the adenomatous polyposis coli (APC) tumor suppressor gene initiates the majority of colorectal (CR) cancers. One consequence of this inactivation is constitutive activation of beta-catenin/Tcf-mediated transcription. To further explore the role of the APC/beta-catenin/Tcf pathway in CR tumorigenesis, we searched for mutations in genes implicated in this pathway in CR tumors lacking APC mutations. No mutations of the gamma-catenin (CTNNG1), GSK-3alpha (GSK3A), or GSK-3beta (GSK3B) genes were detected. In contrast, mutations in the NH2-terminal regulatory domain of beta-catenin (CTNNB1) were found in 13 of 27 (48%) CR tumors lacking APC mutations. Mutations in the beta-catenin regulatory domain and APC were observed to be mutually exclusive, consistent with their equivalent effects on beta-catenin stability and Tcf transactivation. In addition, we found that CTNNB1 mutations can occur in the early, adenomatous stage of CR neoplasia, as has been observed previously with APC mutations. These results suggest that CTNNB1 mutations can uniquely substitute for APC mutations in CR tumors and that beta-catenin signaling plays a critical role in CR tumorigenesis.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>PMID: 9515795</identifier><identifier>CODEN: CNREA8</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Adenocarcinoma - genetics ; Adenoma - genetics ; Amino Acid Sequence ; beta Catenin ; Biological and medical sciences ; Colorectal Neoplasms - genetics ; Cytoskeletal Proteins - genetics ; Desmoplakins ; DNA Mutational Analysis ; gamma Catenin ; Gastroenterology. Liver. Pancreas. Abdomen ; Genes, APC ; Humans ; Medical sciences ; Molecular Sequence Data ; Mutation ; Sequence Alignment ; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus ; TCF Transcription Factors ; Trans-Activators ; Transcription Factor 7-Like 2 Protein ; Transcription Factors - genetics ; Tumors</subject><ispartof>Cancer research (Chicago, Ill.), 1998-03, Vol.58 (6), p.1130-1134</ispartof><rights>1998 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=2190229$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9515795$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>SPARKS, A. B</creatorcontrib><creatorcontrib>MORIN, P. J</creatorcontrib><creatorcontrib>VOGELSTEIN, B</creatorcontrib><creatorcontrib>KINZLER, K. W</creatorcontrib><title>Mutational analysis of the APC/β-catenin/tcf pathway in colorectal cancer</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>Mutation of the adenomatous polyposis coli (APC) tumor suppressor gene initiates the majority of colorectal (CR) cancers. One consequence of this inactivation is constitutive activation of beta-catenin/Tcf-mediated transcription. To further explore the role of the APC/beta-catenin/Tcf pathway in CR tumorigenesis, we searched for mutations in genes implicated in this pathway in CR tumors lacking APC mutations. No mutations of the gamma-catenin (CTNNG1), GSK-3alpha (GSK3A), or GSK-3beta (GSK3B) genes were detected. In contrast, mutations in the NH2-terminal regulatory domain of beta-catenin (CTNNB1) were found in 13 of 27 (48%) CR tumors lacking APC mutations. Mutations in the beta-catenin regulatory domain and APC were observed to be mutually exclusive, consistent with their equivalent effects on beta-catenin stability and Tcf transactivation. In addition, we found that CTNNB1 mutations can occur in the early, adenomatous stage of CR neoplasia, as has been observed previously with APC mutations. These results suggest that CTNNB1 mutations can uniquely substitute for APC mutations in CR tumors and that beta-catenin signaling plays a critical role in CR tumorigenesis.</description><subject>Adenocarcinoma - genetics</subject><subject>Adenoma - genetics</subject><subject>Amino Acid Sequence</subject><subject>beta Catenin</subject><subject>Biological and medical sciences</subject><subject>Colorectal Neoplasms - genetics</subject><subject>Cytoskeletal Proteins - genetics</subject><subject>Desmoplakins</subject><subject>DNA Mutational Analysis</subject><subject>gamma Catenin</subject><subject>Gastroenterology. Liver. Pancreas. Abdomen</subject><subject>Genes, APC</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Molecular Sequence Data</subject><subject>Mutation</subject><subject>Sequence Alignment</subject><subject>Stomach. Duodenum. Small intestine. Colon. Rectum. Anus</subject><subject>TCF Transcription Factors</subject><subject>Trans-Activators</subject><subject>Transcription Factor 7-Like 2 Protein</subject><subject>Transcription Factors - genetics</subject><subject>Tumors</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1998</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkM1Kw0AUhQdRaq0-gjALcRc6_z_LUvxF0YWuw2R6h46kScxMkL6WD-IzGTS4dXMvl_OdA-ceoDmV3BRaCHmI5oQQU0ih2TE6SeltPCUlcoZmVlKprZyj-8chuxzbxtXYjWOfYsJtwHkLePW8Xn59Ft5laGKzzD7gzuXth9vj2GDf1m0PPo9G7xoP_Sk6Cq5OcDbtBXq9vnpZ3xYPTzd369VD0TGlcsGMYr4yIggAywjTEKpqI6wGRaXgVFFnrLZKWkeEBOOB-aCFEcYTGbjlC3T5m9v17fsAKZe7mDzUtWugHVKprZZCcfYvSDWjiv8knk_gUO1gU3Z93Ll-X05fGvWLSXfJuzr0Y9-Y_jBGLWHM8m861HBA</recordid><startdate>19980315</startdate><enddate>19980315</enddate><creator>SPARKS, A. B</creator><creator>MORIN, P. J</creator><creator>VOGELSTEIN, B</creator><creator>KINZLER, K. 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W</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p266t-2862cb84f4ee92027efbbd497e61543161a8979659a045e8ce2cf74848c05f393</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1998</creationdate><topic>Adenocarcinoma - genetics</topic><topic>Adenoma - genetics</topic><topic>Amino Acid Sequence</topic><topic>beta Catenin</topic><topic>Biological and medical sciences</topic><topic>Colorectal Neoplasms - genetics</topic><topic>Cytoskeletal Proteins - genetics</topic><topic>Desmoplakins</topic><topic>DNA Mutational Analysis</topic><topic>gamma Catenin</topic><topic>Gastroenterology. Liver. Pancreas. Abdomen</topic><topic>Genes, APC</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Molecular Sequence Data</topic><topic>Mutation</topic><topic>Sequence Alignment</topic><topic>Stomach. Duodenum. Small intestine. Colon. Rectum. Anus</topic><topic>TCF Transcription Factors</topic><topic>Trans-Activators</topic><topic>Transcription Factor 7-Like 2 Protein</topic><topic>Transcription Factors - genetics</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>SPARKS, A. B</creatorcontrib><creatorcontrib>MORIN, P. J</creatorcontrib><creatorcontrib>VOGELSTEIN, B</creatorcontrib><creatorcontrib>KINZLER, K. 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W</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mutational analysis of the APC/β-catenin/tcf pathway in colorectal cancer</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>1998-03-15</date><risdate>1998</risdate><volume>58</volume><issue>6</issue><spage>1130</spage><epage>1134</epage><pages>1130-1134</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><coden>CNREA8</coden><abstract>Mutation of the adenomatous polyposis coli (APC) tumor suppressor gene initiates the majority of colorectal (CR) cancers. One consequence of this inactivation is constitutive activation of beta-catenin/Tcf-mediated transcription. To further explore the role of the APC/beta-catenin/Tcf pathway in CR tumorigenesis, we searched for mutations in genes implicated in this pathway in CR tumors lacking APC mutations. No mutations of the gamma-catenin (CTNNG1), GSK-3alpha (GSK3A), or GSK-3beta (GSK3B) genes were detected. In contrast, mutations in the NH2-terminal regulatory domain of beta-catenin (CTNNB1) were found in 13 of 27 (48%) CR tumors lacking APC mutations. Mutations in the beta-catenin regulatory domain and APC were observed to be mutually exclusive, consistent with their equivalent effects on beta-catenin stability and Tcf transactivation. In addition, we found that CTNNB1 mutations can occur in the early, adenomatous stage of CR neoplasia, as has been observed previously with APC mutations. These results suggest that CTNNB1 mutations can uniquely substitute for APC mutations in CR tumors and that beta-catenin signaling plays a critical role in CR tumorigenesis.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>9515795</pmid><tpages>5</tpages></addata></record> |
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subjects | Adenocarcinoma - genetics Adenoma - genetics Amino Acid Sequence beta Catenin Biological and medical sciences Colorectal Neoplasms - genetics Cytoskeletal Proteins - genetics Desmoplakins DNA Mutational Analysis gamma Catenin Gastroenterology. Liver. Pancreas. Abdomen Genes, APC Humans Medical sciences Molecular Sequence Data Mutation Sequence Alignment Stomach. Duodenum. Small intestine. Colon. Rectum. Anus TCF Transcription Factors Trans-Activators Transcription Factor 7-Like 2 Protein Transcription Factors - genetics Tumors |
title | Mutational analysis of the APC/β-catenin/tcf pathway in colorectal cancer |
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