Multigene mutational profiling of cholangiocarcinomas identifies actionable molecular subgroups
One-hundred-fifty-three biliary cancers, including 70 intrahepatic cholangiocarcinomas (ICC), 57 extrahepatic cholangiocarcinomas (ECC) and 26 gallbladder carcinomas (GBC) were assessed for mutations in 56 genes using multigene next-generation sequencing. Expression of EGFR and mTOR pathway genes wa...
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| creator | Simbolo, Michele Fassan, Matteo Ruzzenente, Andrea Mafficini, Andrea Wood, Laura D Corbo, Vincenzo Melisi, Davide Malleo, Giuseppe Vicentini, Caterina Malpeli, Giorgio Antonello, Davide Sperandio, Nicola Capelli, Paola Tomezzoli, Anna Iacono, Calogero Lawlor, Rita T Bassi, Claudio Hruban, Ralph H Guglielmi, Alfredo Tortora, Giampaolo de Braud, Filippo Scarpa, Aldo |
| description | One-hundred-fifty-three biliary cancers, including 70 intrahepatic cholangiocarcinomas (ICC), 57 extrahepatic cholangiocarcinomas (ECC) and 26 gallbladder carcinomas (GBC) were assessed for mutations in 56 genes using multigene next-generation sequencing. Expression of EGFR and mTOR pathway genes was investigated by immunohistochemistry. At least one mutated gene was observed in 118/153 (77%) cancers. The genes most frequently involved were KRAS (28%), TP53 (18%), ARID1A (12%), IDH1/2 (9%), PBRM1 (9%), BAP1 (7%), and PIK3CA (7%). IDH1/2 (p=0.0005) and BAP1 (p=0.0097) mutations were characteristic of ICC, while KRAS (p=0.0019) and TP53 (p=0.0019) were more frequent in ECC and GBC. Multivariate analysis identified tumour stage and TP53 mutations as independent predictors of survival. Alterations in chromatin remodeling genes (ARID1A, BAP1, PBRM1, SMARCB1) were seen in 31% of cases. Potentially actionable mutations were seen in 104/153 (68%) cancers: i) KRAS/NRAS/BRAF mutations were found in 34% of cancers; ii) mTOR pathway activation was documented by immunohistochemistry in 51% of cases and by mutations in mTOR pathway genes in 19% of cancers; iii) TGF-ß/Smad signaling was altered in 10.5% cancers; iv) mutations in tyrosine kinase receptors were found in 9% cases. Our study identified molecular subgroups of cholangiocarcinomas that can be explored for specific drug targeting in clinical trials. |
| doi_str_mv | 10.18632/oncotarget.1943 |
| format | Article |
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Expression of EGFR and mTOR pathway genes was investigated by immunohistochemistry. At least one mutated gene was observed in 118/153 (77%) cancers. The genes most frequently involved were KRAS (28%), TP53 (18%), ARID1A (12%), IDH1/2 (9%), PBRM1 (9%), BAP1 (7%), and PIK3CA (7%). IDH1/2 (p=0.0005) and BAP1 (p=0.0097) mutations were characteristic of ICC, while KRAS (p=0.0019) and TP53 (p=0.0019) were more frequent in ECC and GBC. Multivariate analysis identified tumour stage and TP53 mutations as independent predictors of survival. Alterations in chromatin remodeling genes (ARID1A, BAP1, PBRM1, SMARCB1) were seen in 31% of cases. Potentially actionable mutations were seen in 104/153 (68%) cancers: i) KRAS/NRAS/BRAF mutations were found in 34% of cancers; ii) mTOR pathway activation was documented by immunohistochemistry in 51% of cases and by mutations in mTOR pathway genes in 19% of cancers; iii) TGF-ß/Smad signaling was altered in 10.5% cancers; iv) mutations in tyrosine kinase receptors were found in 9% cases. Our study identified molecular subgroups of cholangiocarcinomas that can be explored for specific drug targeting in clinical trials.</description><identifier>ISSN: 1949-2553</identifier><identifier>EISSN: 1949-2553</identifier><identifier>DOI: 10.18632/oncotarget.1943</identifier><identifier>PMID: 24867389</identifier><language>eng</language><publisher>United States: Impact Journals LLC</publisher><subject>Aged ; Bile Duct Neoplasms - genetics ; Bile Duct Neoplasms - mortality ; Bile Duct Neoplasms - pathology ; Bile Ducts, Extrahepatic - metabolism ; Bile Ducts, Extrahepatic - pathology ; Bile Ducts, Intrahepatic - metabolism ; Bile Ducts, Intrahepatic - pathology ; Biomarkers, Tumor - genetics ; Biomarkers, Tumor - metabolism ; Cholangiocarcinoma - classification ; Cholangiocarcinoma - genetics ; Cholangiocarcinoma - mortality ; Cholangiocarcinoma - pathology ; Female ; Follow-Up Studies ; Gallbladder Neoplasms - genetics ; Gallbladder Neoplasms - mortality ; Gallbladder Neoplasms - pathology ; High-Throughput Nucleotide Sequencing ; Humans ; Immunoenzyme Techniques ; In Situ Hybridization, Fluorescence ; Male ; Middle Aged ; Mutation - genetics ; Neoplasm Grading ; Neoplasm Staging ; Prognosis ; Research Paper ; Retrospective Studies ; Survival Rate</subject><ispartof>Oncotarget, 2014-05, Vol.5 (9), p.2839-2852</ispartof><rights>Copyright: © 2014 Simbolo et al. 2014</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c396t-86bbba546a34d5a30af4a583fde6a0aca9b4c5e5f446cb4442d4f4152afbae173</citedby><cites>FETCH-LOGICAL-c396t-86bbba546a34d5a30af4a583fde6a0aca9b4c5e5f446cb4442d4f4152afbae173</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/PMC4058049/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4058049/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27903,27904,53770,53772</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24867389$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Simbolo, Michele</creatorcontrib><creatorcontrib>Fassan, Matteo</creatorcontrib><creatorcontrib>Ruzzenente, Andrea</creatorcontrib><creatorcontrib>Mafficini, Andrea</creatorcontrib><creatorcontrib>Wood, Laura D</creatorcontrib><creatorcontrib>Corbo, Vincenzo</creatorcontrib><creatorcontrib>Melisi, Davide</creatorcontrib><creatorcontrib>Malleo, Giuseppe</creatorcontrib><creatorcontrib>Vicentini, Caterina</creatorcontrib><creatorcontrib>Malpeli, Giorgio</creatorcontrib><creatorcontrib>Antonello, Davide</creatorcontrib><creatorcontrib>Sperandio, Nicola</creatorcontrib><creatorcontrib>Capelli, Paola</creatorcontrib><creatorcontrib>Tomezzoli, Anna</creatorcontrib><creatorcontrib>Iacono, Calogero</creatorcontrib><creatorcontrib>Lawlor, Rita T</creatorcontrib><creatorcontrib>Bassi, Claudio</creatorcontrib><creatorcontrib>Hruban, Ralph H</creatorcontrib><creatorcontrib>Guglielmi, Alfredo</creatorcontrib><creatorcontrib>Tortora, Giampaolo</creatorcontrib><creatorcontrib>de Braud, Filippo</creatorcontrib><creatorcontrib>Scarpa, Aldo</creatorcontrib><title>Multigene mutational profiling of cholangiocarcinomas identifies actionable molecular subgroups</title><title>Oncotarget</title><addtitle>Oncotarget</addtitle><description>One-hundred-fifty-three biliary cancers, including 70 intrahepatic cholangiocarcinomas (ICC), 57 extrahepatic cholangiocarcinomas (ECC) and 26 gallbladder carcinomas (GBC) were assessed for mutations in 56 genes using multigene next-generation sequencing. Expression of EGFR and mTOR pathway genes was investigated by immunohistochemistry. At least one mutated gene was observed in 118/153 (77%) cancers. The genes most frequently involved were KRAS (28%), TP53 (18%), ARID1A (12%), IDH1/2 (9%), PBRM1 (9%), BAP1 (7%), and PIK3CA (7%). IDH1/2 (p=0.0005) and BAP1 (p=0.0097) mutations were characteristic of ICC, while KRAS (p=0.0019) and TP53 (p=0.0019) were more frequent in ECC and GBC. Multivariate analysis identified tumour stage and TP53 mutations as independent predictors of survival. Alterations in chromatin remodeling genes (ARID1A, BAP1, PBRM1, SMARCB1) were seen in 31% of cases. Potentially actionable mutations were seen in 104/153 (68%) cancers: i) KRAS/NRAS/BRAF mutations were found in 34% of cancers; ii) mTOR pathway activation was documented by immunohistochemistry in 51% of cases and by mutations in mTOR pathway genes in 19% of cancers; iii) TGF-ß/Smad signaling was altered in 10.5% cancers; iv) mutations in tyrosine kinase receptors were found in 9% cases. Our study identified molecular subgroups of cholangiocarcinomas that can be explored for specific drug targeting in clinical trials.</description><subject>Aged</subject><subject>Bile Duct Neoplasms - genetics</subject><subject>Bile Duct Neoplasms - mortality</subject><subject>Bile Duct Neoplasms - pathology</subject><subject>Bile Ducts, Extrahepatic - metabolism</subject><subject>Bile Ducts, Extrahepatic - pathology</subject><subject>Bile Ducts, Intrahepatic - metabolism</subject><subject>Bile Ducts, Intrahepatic - pathology</subject><subject>Biomarkers, Tumor - genetics</subject><subject>Biomarkers, Tumor - metabolism</subject><subject>Cholangiocarcinoma - classification</subject><subject>Cholangiocarcinoma - genetics</subject><subject>Cholangiocarcinoma - mortality</subject><subject>Cholangiocarcinoma - pathology</subject><subject>Female</subject><subject>Follow-Up Studies</subject><subject>Gallbladder Neoplasms - genetics</subject><subject>Gallbladder Neoplasms - mortality</subject><subject>Gallbladder Neoplasms - pathology</subject><subject>High-Throughput Nucleotide Sequencing</subject><subject>Humans</subject><subject>Immunoenzyme Techniques</subject><subject>In Situ Hybridization, Fluorescence</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Mutation - genetics</subject><subject>Neoplasm Grading</subject><subject>Neoplasm Staging</subject><subject>Prognosis</subject><subject>Research Paper</subject><subject>Retrospective Studies</subject><subject>Survival Rate</subject><issn>1949-2553</issn><issn>1949-2553</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUTtPwzAQthCIVqU7E8rI0uLEjyYLEqp4SUUsMFtnx06NnDjYCRL_nvRBKbfcSXff4_QhdJnieZpzkt34RvkOQqW7eVpQcoLGQytmGWPk9GgeoWmMH3goRhd5VpyjUUZzviB5MUbipXedrXSjk7rvoLO-AZe0wRvrbFMl3iRq7R00lfUKgrKNryEmttRNZ43VMQG1BUk3MHinVe8gJLGXVfB9Gy_QmQEX9XTfJ-j94f5t-TRbvT4-L-9WM0UK3s1yLqUERjkQWjIgGAwFlhNTag4YFBSSKqaZoZQrSSnNSmpoyjIwEnS6IBN0u-Nte1nrUg32AjjRBltD-BYerPi_aexaVP5LUMxyTIuB4HpPEPxnr2MnahuVdsPr2vdRpIxgkhacbbTw7lQFH2PQ5iCTYrGNRvxFIzbRDJCrY3sHwG8Q5AfIy5H2</recordid><startdate>20140515</startdate><enddate>20140515</enddate><creator>Simbolo, Michele</creator><creator>Fassan, Matteo</creator><creator>Ruzzenente, Andrea</creator><creator>Mafficini, Andrea</creator><creator>Wood, Laura D</creator><creator>Corbo, Vincenzo</creator><creator>Melisi, Davide</creator><creator>Malleo, Giuseppe</creator><creator>Vicentini, Caterina</creator><creator>Malpeli, Giorgio</creator><creator>Antonello, Davide</creator><creator>Sperandio, Nicola</creator><creator>Capelli, Paola</creator><creator>Tomezzoli, Anna</creator><creator>Iacono, Calogero</creator><creator>Lawlor, Rita T</creator><creator>Bassi, Claudio</creator><creator>Hruban, Ralph H</creator><creator>Guglielmi, Alfredo</creator><creator>Tortora, Giampaolo</creator><creator>de Braud, Filippo</creator><creator>Scarpa, Aldo</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>20140515</creationdate><title>Multigene mutational profiling of cholangiocarcinomas identifies actionable molecular subgroups</title><author>Simbolo, Michele ; Fassan, Matteo ; Ruzzenente, Andrea ; Mafficini, Andrea ; Wood, Laura D ; Corbo, Vincenzo ; Melisi, Davide ; Malleo, Giuseppe ; Vicentini, Caterina ; Malpeli, Giorgio ; Antonello, Davide ; Sperandio, Nicola ; Capelli, Paola ; Tomezzoli, Anna ; Iacono, Calogero ; Lawlor, Rita T ; Bassi, Claudio ; Hruban, Ralph H ; Guglielmi, Alfredo ; Tortora, Giampaolo ; de Braud, Filippo ; Scarpa, Aldo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c396t-86bbba546a34d5a30af4a583fde6a0aca9b4c5e5f446cb4442d4f4152afbae173</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Aged</topic><topic>Bile Duct Neoplasms - genetics</topic><topic>Bile Duct Neoplasms - mortality</topic><topic>Bile Duct Neoplasms - pathology</topic><topic>Bile Ducts, Extrahepatic - metabolism</topic><topic>Bile Ducts, Extrahepatic - pathology</topic><topic>Bile Ducts, Intrahepatic - metabolism</topic><topic>Bile Ducts, Intrahepatic - pathology</topic><topic>Biomarkers, Tumor - genetics</topic><topic>Biomarkers, Tumor - metabolism</topic><topic>Cholangiocarcinoma - classification</topic><topic>Cholangiocarcinoma - genetics</topic><topic>Cholangiocarcinoma - mortality</topic><topic>Cholangiocarcinoma - pathology</topic><topic>Female</topic><topic>Follow-Up Studies</topic><topic>Gallbladder Neoplasms - genetics</topic><topic>Gallbladder Neoplasms - mortality</topic><topic>Gallbladder Neoplasms - pathology</topic><topic>High-Throughput Nucleotide Sequencing</topic><topic>Humans</topic><topic>Immunoenzyme Techniques</topic><topic>In Situ Hybridization, Fluorescence</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Mutation - genetics</topic><topic>Neoplasm Grading</topic><topic>Neoplasm Staging</topic><topic>Prognosis</topic><topic>Research Paper</topic><topic>Retrospective Studies</topic><topic>Survival Rate</topic><toplevel>online_resources</toplevel><creatorcontrib>Simbolo, Michele</creatorcontrib><creatorcontrib>Fassan, Matteo</creatorcontrib><creatorcontrib>Ruzzenente, Andrea</creatorcontrib><creatorcontrib>Mafficini, Andrea</creatorcontrib><creatorcontrib>Wood, Laura D</creatorcontrib><creatorcontrib>Corbo, Vincenzo</creatorcontrib><creatorcontrib>Melisi, Davide</creatorcontrib><creatorcontrib>Malleo, Giuseppe</creatorcontrib><creatorcontrib>Vicentini, Caterina</creatorcontrib><creatorcontrib>Malpeli, Giorgio</creatorcontrib><creatorcontrib>Antonello, Davide</creatorcontrib><creatorcontrib>Sperandio, Nicola</creatorcontrib><creatorcontrib>Capelli, Paola</creatorcontrib><creatorcontrib>Tomezzoli, Anna</creatorcontrib><creatorcontrib>Iacono, Calogero</creatorcontrib><creatorcontrib>Lawlor, Rita T</creatorcontrib><creatorcontrib>Bassi, Claudio</creatorcontrib><creatorcontrib>Hruban, Ralph H</creatorcontrib><creatorcontrib>Guglielmi, Alfredo</creatorcontrib><creatorcontrib>Tortora, Giampaolo</creatorcontrib><creatorcontrib>de Braud, Filippo</creatorcontrib><creatorcontrib>Scarpa, Aldo</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>Simbolo, Michele</au><au>Fassan, Matteo</au><au>Ruzzenente, Andrea</au><au>Mafficini, Andrea</au><au>Wood, Laura D</au><au>Corbo, Vincenzo</au><au>Melisi, Davide</au><au>Malleo, Giuseppe</au><au>Vicentini, Caterina</au><au>Malpeli, Giorgio</au><au>Antonello, Davide</au><au>Sperandio, Nicola</au><au>Capelli, Paola</au><au>Tomezzoli, Anna</au><au>Iacono, Calogero</au><au>Lawlor, Rita T</au><au>Bassi, Claudio</au><au>Hruban, Ralph H</au><au>Guglielmi, Alfredo</au><au>Tortora, Giampaolo</au><au>de Braud, Filippo</au><au>Scarpa, Aldo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Multigene mutational profiling of cholangiocarcinomas identifies actionable molecular subgroups</atitle><jtitle>Oncotarget</jtitle><addtitle>Oncotarget</addtitle><date>2014-05-15</date><risdate>2014</risdate><volume>5</volume><issue>9</issue><spage>2839</spage><epage>2852</epage><pages>2839-2852</pages><issn>1949-2553</issn><eissn>1949-2553</eissn><abstract>One-hundred-fifty-three biliary cancers, including 70 intrahepatic cholangiocarcinomas (ICC), 57 extrahepatic cholangiocarcinomas (ECC) and 26 gallbladder carcinomas (GBC) were assessed for mutations in 56 genes using multigene next-generation sequencing. Expression of EGFR and mTOR pathway genes was investigated by immunohistochemistry. At least one mutated gene was observed in 118/153 (77%) cancers. The genes most frequently involved were KRAS (28%), TP53 (18%), ARID1A (12%), IDH1/2 (9%), PBRM1 (9%), BAP1 (7%), and PIK3CA (7%). IDH1/2 (p=0.0005) and BAP1 (p=0.0097) mutations were characteristic of ICC, while KRAS (p=0.0019) and TP53 (p=0.0019) were more frequent in ECC and GBC. Multivariate analysis identified tumour stage and TP53 mutations as independent predictors of survival. Alterations in chromatin remodeling genes (ARID1A, BAP1, PBRM1, SMARCB1) were seen in 31% of cases. Potentially actionable mutations were seen in 104/153 (68%) cancers: i) KRAS/NRAS/BRAF mutations were found in 34% of cancers; ii) mTOR pathway activation was documented by immunohistochemistry in 51% of cases and by mutations in mTOR pathway genes in 19% of cancers; iii) TGF-ß/Smad signaling was altered in 10.5% cancers; iv) mutations in tyrosine kinase receptors were found in 9% cases. Our study identified molecular subgroups of cholangiocarcinomas that can be explored for specific drug targeting in clinical trials.</abstract><cop>United States</cop><pub>Impact Journals LLC</pub><pmid>24867389</pmid><doi>10.18632/oncotarget.1943</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Aged Bile Duct Neoplasms - genetics Bile Duct Neoplasms - mortality Bile Duct Neoplasms - pathology Bile Ducts, Extrahepatic - metabolism Bile Ducts, Extrahepatic - pathology Bile Ducts, Intrahepatic - metabolism Bile Ducts, Intrahepatic - pathology Biomarkers, Tumor - genetics Biomarkers, Tumor - metabolism Cholangiocarcinoma - classification Cholangiocarcinoma - genetics Cholangiocarcinoma - mortality Cholangiocarcinoma - pathology Female Follow-Up Studies Gallbladder Neoplasms - genetics Gallbladder Neoplasms - mortality Gallbladder Neoplasms - pathology High-Throughput Nucleotide Sequencing Humans Immunoenzyme Techniques In Situ Hybridization, Fluorescence Male Middle Aged Mutation - genetics Neoplasm Grading Neoplasm Staging Prognosis Research Paper Retrospective Studies Survival Rate |
| title | Multigene mutational profiling of cholangiocarcinomas identifies actionable molecular subgroups |
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