Isocitrate dehydrogenase 1 and 2 mutations in cholangiocarcinoma
Summary Somatic mutations in isocitrate dehydrogenase 1 and 2 genes are common in gliomas and help stratify patients with brain cancer into histologic and molecular subtypes. However, these mutations are considered rare in other solid tumors. The aims of this study were to determine the frequency of...
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| creator | Kipp, Benjamin R., PhD Voss, Jesse S., BS, CT, MB(ASCP) Kerr, Sarah E., MD Barr Fritcher, Emily G., BA, CT, MB(ASCP) Graham, Rondell P., MBBS Zhang, Lizhi, MD Highsmith, W. Edward, PhD Zhang, Jun, MD Roberts, Lewis R., MB, ChB, PhD Gores, Gregory J., MD Halling, Kevin C., MD, PhD |
| description | Summary Somatic mutations in isocitrate dehydrogenase 1 and 2 genes are common in gliomas and help stratify patients with brain cancer into histologic and molecular subtypes. However, these mutations are considered rare in other solid tumors. The aims of this study were to determine the frequency of isocitrate dehydrogenase 1 and 2 mutations in cholangiocarcinoma and to assess histopathologic differences between specimens with and without an isocitrate dehydrogenase mutation. We sequenced 94 formalin-fixed, paraffin-embedded cholangiocarcinoma (67 intrahepatic and 27 extrahepatic) assessing for isocitrate dehydrogenase 1 (codon 132) and isocitrate dehydrogenase 2 (codons 140 and 172) mutations. Multiple histopathologic characteristics were also evaluated and compared with isocitrate dehydrogenase 1/2 mutation status. Of the 94 evaluated specimens, 21 (22%) had a mutation including 14 isocitrate dehydrogenase 1 and 7 isocitrate dehydrogenase 2 mutations. Isocitrate dehydrogenase mutations were more frequently observed in intrahepatic cholangiocarcinoma than in extrahepatic cholangiocarcinoma (28% versus 7%, respectively; P = .030). The 14 isocitrate dehydrogenase 1 mutations were R132C (n = 9), R132S (n = 2), R132G (n = 2), and R132L (n = 1). The 7 isocitrate dehydrogenase 2 mutations were R172K (n = 5), R172M (n = 1), and R172G (n = 1). Isocitrate dehydrogenase mutations were more frequently observed in tumors with clear cell change ( P < .001) and poorly differentiated histology ( P = .012). The results of this study show for the first time that isocitrate dehydrogenase 1 and 2 genes are mutated in cholangiocarcinoma. The results of this study are encouraging because it identifies a new potential target for genotype-directed therapeutic trials and may represent a potential biomarker for earlier detection of cholangiocarcinoma in a subset of cases. |
| doi_str_mv | 10.1016/j.humpath.2011.12.007 |
| format | Article |
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Edward, PhD ; Zhang, Jun, MD ; Roberts, Lewis R., MB, ChB, PhD ; Gores, Gregory J., MD ; Halling, Kevin C., MD, PhD</creator><creatorcontrib>Kipp, Benjamin R., PhD ; Voss, Jesse S., BS, CT, MB(ASCP) ; Kerr, Sarah E., MD ; Barr Fritcher, Emily G., BA, CT, MB(ASCP) ; Graham, Rondell P., MBBS ; Zhang, Lizhi, MD ; Highsmith, W. Edward, PhD ; Zhang, Jun, MD ; Roberts, Lewis R., MB, ChB, PhD ; Gores, Gregory J., MD ; Halling, Kevin C., MD, PhD</creatorcontrib><description>Summary Somatic mutations in isocitrate dehydrogenase 1 and 2 genes are common in gliomas and help stratify patients with brain cancer into histologic and molecular subtypes. However, these mutations are considered rare in other solid tumors. The aims of this study were to determine the frequency of isocitrate dehydrogenase 1 and 2 mutations in cholangiocarcinoma and to assess histopathologic differences between specimens with and without an isocitrate dehydrogenase mutation. We sequenced 94 formalin-fixed, paraffin-embedded cholangiocarcinoma (67 intrahepatic and 27 extrahepatic) assessing for isocitrate dehydrogenase 1 (codon 132) and isocitrate dehydrogenase 2 (codons 140 and 172) mutations. Multiple histopathologic characteristics were also evaluated and compared with isocitrate dehydrogenase 1/2 mutation status. Of the 94 evaluated specimens, 21 (22%) had a mutation including 14 isocitrate dehydrogenase 1 and 7 isocitrate dehydrogenase 2 mutations. Isocitrate dehydrogenase mutations were more frequently observed in intrahepatic cholangiocarcinoma than in extrahepatic cholangiocarcinoma (28% versus 7%, respectively; P = .030). The 14 isocitrate dehydrogenase 1 mutations were R132C (n = 9), R132S (n = 2), R132G (n = 2), and R132L (n = 1). The 7 isocitrate dehydrogenase 2 mutations were R172K (n = 5), R172M (n = 1), and R172G (n = 1). Isocitrate dehydrogenase mutations were more frequently observed in tumors with clear cell change ( P < .001) and poorly differentiated histology ( P = .012). The results of this study show for the first time that isocitrate dehydrogenase 1 and 2 genes are mutated in cholangiocarcinoma. The results of this study are encouraging because it identifies a new potential target for genotype-directed therapeutic trials and may represent a potential biomarker for earlier detection of cholangiocarcinoma in a subset of cases.</description><identifier>ISSN: 0046-8177</identifier><identifier>EISSN: 1532-8392</identifier><identifier>DOI: 10.1016/j.humpath.2011.12.007</identifier><identifier>PMID: 22503487</identifier><identifier>CODEN: HPCQA4</identifier><language>eng</language><publisher>New York, NY: Elsevier Inc</publisher><subject>2-hydroxyglutarate ; Base Sequence ; Bile duct ; Bile Duct Neoplasms - genetics ; Bile Duct Neoplasms - pathology ; Bile Ducts, Intrahepatic - pathology ; Biliary tract ; Biological and medical sciences ; Cancer ; Cholangiocarcinoma ; Cholangiocarcinoma - genetics ; Cholangiocarcinoma - pathology ; Female ; Gastroenterology. Liver. Pancreas. Abdomen ; Genes ; Humans ; Investigative techniques, diagnostic techniques (general aspects) ; Isocitrate dehydrogenase ; Isocitrate Dehydrogenase - genetics ; Liver. Biliary tract. Portal circulation. Exocrine pancreas ; Male ; Medical sciences ; Middle Aged ; Mutation ; Pathology ; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques ; Reverse Transcriptase Polymerase Chain Reaction ; Studies ; Tumors</subject><ispartof>Human pathology, 2012-10, Vol.43 (10), p.1552-1558</ispartof><rights>Elsevier Inc.</rights><rights>2012 Elsevier Inc.</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2012 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c478t-b9e55980e4141d3be8cbf9f02fe4e143066c1b0e46733fe1c5def0bb48f8cea3</citedby><cites>FETCH-LOGICAL-c478t-b9e55980e4141d3be8cbf9f02fe4e143066c1b0e46733fe1c5def0bb48f8cea3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.humpath.2011.12.007$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,777,781,3537,27905,27906,45976</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26426057$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22503487$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kipp, Benjamin R., PhD</creatorcontrib><creatorcontrib>Voss, Jesse S., BS, CT, MB(ASCP)</creatorcontrib><creatorcontrib>Kerr, Sarah E., MD</creatorcontrib><creatorcontrib>Barr Fritcher, Emily G., BA, CT, MB(ASCP)</creatorcontrib><creatorcontrib>Graham, Rondell P., MBBS</creatorcontrib><creatorcontrib>Zhang, Lizhi, MD</creatorcontrib><creatorcontrib>Highsmith, W. Edward, PhD</creatorcontrib><creatorcontrib>Zhang, Jun, MD</creatorcontrib><creatorcontrib>Roberts, Lewis R., MB, ChB, PhD</creatorcontrib><creatorcontrib>Gores, Gregory J., MD</creatorcontrib><creatorcontrib>Halling, Kevin C., MD, PhD</creatorcontrib><title>Isocitrate dehydrogenase 1 and 2 mutations in cholangiocarcinoma</title><title>Human pathology</title><addtitle>Hum Pathol</addtitle><description>Summary Somatic mutations in isocitrate dehydrogenase 1 and 2 genes are common in gliomas and help stratify patients with brain cancer into histologic and molecular subtypes. However, these mutations are considered rare in other solid tumors. The aims of this study were to determine the frequency of isocitrate dehydrogenase 1 and 2 mutations in cholangiocarcinoma and to assess histopathologic differences between specimens with and without an isocitrate dehydrogenase mutation. We sequenced 94 formalin-fixed, paraffin-embedded cholangiocarcinoma (67 intrahepatic and 27 extrahepatic) assessing for isocitrate dehydrogenase 1 (codon 132) and isocitrate dehydrogenase 2 (codons 140 and 172) mutations. Multiple histopathologic characteristics were also evaluated and compared with isocitrate dehydrogenase 1/2 mutation status. Of the 94 evaluated specimens, 21 (22%) had a mutation including 14 isocitrate dehydrogenase 1 and 7 isocitrate dehydrogenase 2 mutations. Isocitrate dehydrogenase mutations were more frequently observed in intrahepatic cholangiocarcinoma than in extrahepatic cholangiocarcinoma (28% versus 7%, respectively; P = .030). The 14 isocitrate dehydrogenase 1 mutations were R132C (n = 9), R132S (n = 2), R132G (n = 2), and R132L (n = 1). The 7 isocitrate dehydrogenase 2 mutations were R172K (n = 5), R172M (n = 1), and R172G (n = 1). Isocitrate dehydrogenase mutations were more frequently observed in tumors with clear cell change ( P < .001) and poorly differentiated histology ( P = .012). The results of this study show for the first time that isocitrate dehydrogenase 1 and 2 genes are mutated in cholangiocarcinoma. The results of this study are encouraging because it identifies a new potential target for genotype-directed therapeutic trials and may represent a potential biomarker for earlier detection of cholangiocarcinoma in a subset of cases.</description><subject>2-hydroxyglutarate</subject><subject>Base Sequence</subject><subject>Bile duct</subject><subject>Bile Duct Neoplasms - genetics</subject><subject>Bile Duct Neoplasms - pathology</subject><subject>Bile Ducts, Intrahepatic - pathology</subject><subject>Biliary tract</subject><subject>Biological and medical sciences</subject><subject>Cancer</subject><subject>Cholangiocarcinoma</subject><subject>Cholangiocarcinoma - genetics</subject><subject>Cholangiocarcinoma - pathology</subject><subject>Female</subject><subject>Gastroenterology. Liver. Pancreas. Abdomen</subject><subject>Genes</subject><subject>Humans</subject><subject>Investigative techniques, diagnostic techniques (general aspects)</subject><subject>Isocitrate dehydrogenase</subject><subject>Isocitrate Dehydrogenase - genetics</subject><subject>Liver. Biliary tract. Portal circulation. Exocrine pancreas</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Mutation</subject><subject>Pathology</subject><subject>Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>Studies</subject><subject>Tumors</subject><issn>0046-8177</issn><issn>1532-8392</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkt2L1DAUxYMo7rj6JygFEXzpeG-atOmLHyx-LCz44L6HNL3dydgmY9IK89-bMqML--JTCPmdk3MPl7GXCFsErN_tt7tlOph5t-WAuEW-BWgesQ3KipeqavljtgEQdamwaS7Ys5T2kEEp5FN2wbmESqhmwz5ep2DdHM1MRU-7Yx_DHXmTqMDC-L7gxbTMZnbBp8L5wu7CaPydC9ZE63yYzHP2ZDBjohfn85Ldfvl8e_WtvPn-9frq001pRaPmsmtJylYBCRTYVx0p2w3tAHwgQSgqqGuLXX6um6oaCK3saYCuE2pQlkx1yd6ebA8x_FoozXpyydKY01BYkkaoWw6tapuMvn6A7sMSfQ6XKQUttrKGTMkTZWNIKdKgD9FNJh4zpNeG9V6fG9Zrwxq5zg1n3auz-9JN1P9T_a00A2_OgEnWjEM03rp0z9WC1yBX7sOJo9zab0dRJ-vIW-pdJDvrPrj_Rnn_wMGOzrv86U86UrqfWqcs0D_WdVi3ARFA5kv1B0jGsCY</recordid><startdate>20121001</startdate><enddate>20121001</enddate><creator>Kipp, Benjamin R., PhD</creator><creator>Voss, Jesse S., BS, CT, MB(ASCP)</creator><creator>Kerr, Sarah E., MD</creator><creator>Barr Fritcher, Emily G., BA, CT, MB(ASCP)</creator><creator>Graham, Rondell P., MBBS</creator><creator>Zhang, Lizhi, MD</creator><creator>Highsmith, W. Edward, PhD</creator><creator>Zhang, Jun, MD</creator><creator>Roberts, Lewis R., MB, ChB, PhD</creator><creator>Gores, Gregory J., MD</creator><creator>Halling, Kevin C., MD, PhD</creator><general>Elsevier Inc</general><general>Elsevier</general><general>Elsevier Limited</general><scope>IQODW</scope><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>K9.</scope><scope>7X8</scope></search><sort><creationdate>20121001</creationdate><title>Isocitrate dehydrogenase 1 and 2 mutations in cholangiocarcinoma</title><author>Kipp, Benjamin R., PhD ; Voss, Jesse S., BS, CT, MB(ASCP) ; Kerr, Sarah E., MD ; Barr Fritcher, Emily G., BA, CT, MB(ASCP) ; Graham, Rondell P., MBBS ; Zhang, Lizhi, MD ; Highsmith, W. Edward, PhD ; Zhang, Jun, MD ; Roberts, Lewis R., MB, ChB, PhD ; Gores, Gregory J., MD ; Halling, Kevin C., MD, PhD</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c478t-b9e55980e4141d3be8cbf9f02fe4e143066c1b0e46733fe1c5def0bb48f8cea3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>2-hydroxyglutarate</topic><topic>Base Sequence</topic><topic>Bile duct</topic><topic>Bile Duct Neoplasms - genetics</topic><topic>Bile Duct Neoplasms - pathology</topic><topic>Bile Ducts, Intrahepatic - pathology</topic><topic>Biliary tract</topic><topic>Biological and medical sciences</topic><topic>Cancer</topic><topic>Cholangiocarcinoma</topic><topic>Cholangiocarcinoma - genetics</topic><topic>Cholangiocarcinoma - pathology</topic><topic>Female</topic><topic>Gastroenterology. Liver. Pancreas. Abdomen</topic><topic>Genes</topic><topic>Humans</topic><topic>Investigative techniques, diagnostic techniques (general aspects)</topic><topic>Isocitrate dehydrogenase</topic><topic>Isocitrate Dehydrogenase - genetics</topic><topic>Liver. Biliary tract. Portal circulation. Exocrine pancreas</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>Mutation</topic><topic>Pathology</topic><topic>Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>Studies</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kipp, Benjamin R., PhD</creatorcontrib><creatorcontrib>Voss, Jesse S., BS, CT, MB(ASCP)</creatorcontrib><creatorcontrib>Kerr, Sarah E., MD</creatorcontrib><creatorcontrib>Barr Fritcher, Emily G., BA, CT, MB(ASCP)</creatorcontrib><creatorcontrib>Graham, Rondell P., MBBS</creatorcontrib><creatorcontrib>Zhang, Lizhi, MD</creatorcontrib><creatorcontrib>Highsmith, W. Edward, PhD</creatorcontrib><creatorcontrib>Zhang, Jun, MD</creatorcontrib><creatorcontrib>Roberts, Lewis R., MB, ChB, PhD</creatorcontrib><creatorcontrib>Gores, Gregory J., MD</creatorcontrib><creatorcontrib>Halling, Kevin C., MD, PhD</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>Human pathology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kipp, Benjamin R., PhD</au><au>Voss, Jesse S., BS, CT, MB(ASCP)</au><au>Kerr, Sarah E., MD</au><au>Barr Fritcher, Emily G., BA, CT, MB(ASCP)</au><au>Graham, Rondell P., MBBS</au><au>Zhang, Lizhi, MD</au><au>Highsmith, W. Edward, PhD</au><au>Zhang, Jun, MD</au><au>Roberts, Lewis R., MB, ChB, PhD</au><au>Gores, Gregory J., MD</au><au>Halling, Kevin C., MD, PhD</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Isocitrate dehydrogenase 1 and 2 mutations in cholangiocarcinoma</atitle><jtitle>Human pathology</jtitle><addtitle>Hum Pathol</addtitle><date>2012-10-01</date><risdate>2012</risdate><volume>43</volume><issue>10</issue><spage>1552</spage><epage>1558</epage><pages>1552-1558</pages><issn>0046-8177</issn><eissn>1532-8392</eissn><coden>HPCQA4</coden><abstract>Summary Somatic mutations in isocitrate dehydrogenase 1 and 2 genes are common in gliomas and help stratify patients with brain cancer into histologic and molecular subtypes. However, these mutations are considered rare in other solid tumors. The aims of this study were to determine the frequency of isocitrate dehydrogenase 1 and 2 mutations in cholangiocarcinoma and to assess histopathologic differences between specimens with and without an isocitrate dehydrogenase mutation. We sequenced 94 formalin-fixed, paraffin-embedded cholangiocarcinoma (67 intrahepatic and 27 extrahepatic) assessing for isocitrate dehydrogenase 1 (codon 132) and isocitrate dehydrogenase 2 (codons 140 and 172) mutations. Multiple histopathologic characteristics were also evaluated and compared with isocitrate dehydrogenase 1/2 mutation status. Of the 94 evaluated specimens, 21 (22%) had a mutation including 14 isocitrate dehydrogenase 1 and 7 isocitrate dehydrogenase 2 mutations. Isocitrate dehydrogenase mutations were more frequently observed in intrahepatic cholangiocarcinoma than in extrahepatic cholangiocarcinoma (28% versus 7%, respectively; P = .030). The 14 isocitrate dehydrogenase 1 mutations were R132C (n = 9), R132S (n = 2), R132G (n = 2), and R132L (n = 1). The 7 isocitrate dehydrogenase 2 mutations were R172K (n = 5), R172M (n = 1), and R172G (n = 1). Isocitrate dehydrogenase mutations were more frequently observed in tumors with clear cell change ( P < .001) and poorly differentiated histology ( P = .012). The results of this study show for the first time that isocitrate dehydrogenase 1 and 2 genes are mutated in cholangiocarcinoma. The results of this study are encouraging because it identifies a new potential target for genotype-directed therapeutic trials and may represent a potential biomarker for earlier detection of cholangiocarcinoma in a subset of cases.</abstract><cop>New York, NY</cop><pub>Elsevier Inc</pub><pmid>22503487</pmid><doi>10.1016/j.humpath.2011.12.007</doi><tpages>7</tpages></addata></record> |
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| subjects | 2-hydroxyglutarate Base Sequence Bile duct Bile Duct Neoplasms - genetics Bile Duct Neoplasms - pathology Bile Ducts, Intrahepatic - pathology Biliary tract Biological and medical sciences Cancer Cholangiocarcinoma Cholangiocarcinoma - genetics Cholangiocarcinoma - pathology Female Gastroenterology. Liver. Pancreas. Abdomen Genes Humans Investigative techniques, diagnostic techniques (general aspects) Isocitrate dehydrogenase Isocitrate Dehydrogenase - genetics Liver. Biliary tract. Portal circulation. Exocrine pancreas Male Medical sciences Middle Aged Mutation Pathology Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques Reverse Transcriptase Polymerase Chain Reaction Studies Tumors |
| title | Isocitrate dehydrogenase 1 and 2 mutations in cholangiocarcinoma |
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