Cholangiocarcinoma (CCA) is an aggressive malignancy of the bile ducts, with poor prognosis and limited treatment options. Here, we describe the integrated analysis of somatic mutations, RNA expression, copy number, and DNA methylation by The Cancer Genome Atlas, of a set of predominantly intrahepatic CCA cases, and propose a molecular classification scheme. We identified an IDH-mutant enriched subtype with distinct molecular features including low expression of chromatin modifiers, elevated expression of mitochondrial genes, and increased mitochondrial DNA copy number. Leveraging the multi-platform data, we observed that ARID1A exhibited DNA hypermethylation and decreased expression in the IDH-mutant subtype. More broadly, we found that IDH mutations are associated with an expanded histological spectrum of liver tumors with molecular features that stratify with CCA. Our studies reveal insights into the molecular pathogenesis and heterogeneity of cholangiocarcinoma and provide classification information of potential therapeutic significance.

Erratum: Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles (Cell Reports (2017) 18(11) (2780–2794) (S2211124717302140) (10.1016/j.celrep.2017.02.033)) / Farshidfar, Farshad; Zheng, Siyuan; Gingras, Marie Claude; Newton, Yulia; Shih, Juliann; Robertson, A. Gordon; Hinoue, Toshinori; Hoadley, Katherine A.; Gibb, Ewan A.; Roszik, Jason; Covington, Kyle R.; Wu, Chia Chin; Shinbrot, Eve; Stransky, Nicolas; Hegde, Apurva; Yang, Ju Dong; Reznik, Ed; Sadeghi, Sara; Pedamallu, Chandra Sekhar; Ojesina, Akinyemi I.; Hess, Julian M.; Auman, J. Todd; Rhie, Suhn K.; Bowlby, Reanne; Borad, Mitesh J.; Akbani, Rehan; Allotey, Loretta K.; Ally, Adrian; Alvaro, Domenico; Andersen, Jesper B.; Appelbaum, Elizabeth L.; Arora, Arshi; Auman, J. Todd; Balasundaram, Miruna; Balu, Saianand; Bardeesy, Nabeel; Bathe, Oliver F.; Baylin, Stephen B.; Beroukhim, Rameen; Berrios, Mario; Bodenheimer, Tom; Boice, Lori; Bootwalla, Moiz S.; Borad, Mitesh J.; Bowen, Jay; Bowlby, Reanne; Bragazzi, MARIA CONSIGLIA; Brooks, Denise; Cardinale, Vincenzo; Carlsen, Rebecca; Carpino, Guido; Carvalho, Andre L.; Chaiteerakij, Roongruedee; Chandan, Vishal C.; Cherniack, Andrew D.; Chin, Lynda; Cho, Juok; Choe, Gina; Chuah, Eric; Chudamani, Sudha; Cibulskis, Carrie; Cordes, Matthew G.; Covington, Kyle R.; Crain, Daniel; Curley, Erin; De Rose, Agostino Maria; Defreitas, Timothy; Demchok, John A.; Deshpande, Vikram; Dhalla, Noreen; Ding, Li; Evason, Kimberley; Farshidfar, Farshad; Felau, Ina; Ferguson, Martin L.; Foo, Wai Chin; Franchitto, Antonio; Frazer, Scott; Fronick, Catrina C.; Fulton, Lucinda A.; Fulton, Robert S.; Gabriel, Stacey B.; Gardner, Johanna; Gastier Foster, Julie M.; Gaudio, Eugenio; Gehlenborg, Nils; Genovese, Giannicola; Gerken, Mark; Getz, Gad; Giama, Nasra H.; Gibbs, Richard A.; Gingras, Marie Claude; Giuliante, Felice; Grazi, Gian Luca; Hayes, D. Neil; Hegde, Apurva M.; Heiman, David I.; Hess, Julian M.; Hinoue, Toshinori; Hoadley, Katherine A.; Holbrook, Andrea; Holt, Robert A.; Hoyle, Alan P.; Huang, Mei; Hutter, Carolyn M.; Jefferys, Stuart R.; Jones, Steven J. M.; Jones, Corbin D.; Kasaian, Katayoon; Kelley, Robin K.; Kim, Jaegil; Kleiner, David E.; Kocher, Jean Pierre A.; Kwong, Lawrence N.; Lai, Phillip H.; Laird, Peter W.; Lawrence, Michael S.; Leraas, Kristen M.; Lichtenberg, Tara M.; Lin, Pei; Liu, Wenbin; Liu, Jia; Lolla, Laxmi; Lu, Yiling; Ma, Yussanne; Mallery, David; Mardis, Elaine R.; Marra, Marco A.; Matsushita, Marcus M.; Mayo, Michael; Mclellan, Michael D.; Mcree, Autumn J.; Meier, Sam; Meng, Shaowu; Meyerson, Matthew; Mieczkowski, Piotr A.; Miller, Christopher A.; Mills, Gordon B.; Moore, Richard A.; Morris, Scott; Mose, Lisle E.; Moser, Catherine D.; Mounajjed, Taofic; Mungall, Andrew J.; Mungall, Karen; Murray, Bradley A.; Naresh, Rashi; Newton, Yulia; Noble, Michael S.; O'Brien, Daniel R.; Ojesina, Akinyemi I.; Parker, Joel S.; Patel, Tushar C.; Paulauskis, Joseph; Pedamallu, Chandra Sekhar; Penny, Robert; Perou, Charles M.; Perou, Amy H.; Pihl, Todd; Radenbaugh, Amie J.; Ramirez, Nilsa C.; Rathmell, W. Kimryn; Reznik, Ed; Rhie, Suhn K.; Roach, Jeffrey; Roberts, Lewis R.; Robertson, A. Gordon; Sadeghi, Sara; Saksena, Gordon; Sander, Chris; Schein, Jacqueline E.; Schmidt, Heather K.; Schumacher, Steven E.; Shelton, Candace; Shelton, Troy; Shen, Ronglai; Sheth, Margi; Shi, Yan; Shih, Juliann; Shinbrot, Eve; Shroff, Rachna; Simons, Janae V.; Sipahimalani, Payal; Skelly, Tara; Sofia, Heidi J.; Soloway, Matthew G.; Stoppler, Hubert; Stransky, Nicolas; Stuart, Josh; Sun, Qiang; Tam, Angela; Tan, Donghui; Tarnuzzer, Roy; Thiessen, Nina; Thorne, Leigh B.; Torbenson, Michael S.; Van Den Berg, David J.; Veluvolu, Umadevi; Verhaak, Roel G. W.; Voet, Doug; Wan, Yunhu; Wang, Zhining; Weinstein, John N.; Weisenberger, Daniel J.; Wheeler, David A.; Wilson, Richard K.; Wise, Lisa; Wong, Tina; Wu, Chia Chin; Wu, Ye; Xi, Liu; Yang, Ju Dong; Yang, Liming; Zenklusen, Jean C.; Zhang, Hailei; Zhang, Jiashan; Zheng, Siyuan; Zmuda, Erik; Zhu, Andrew X.; Stuart, Josh M.; Sander, Chris; Akbani, Rehan; Cherniack, Andrew D.; Deshpande, Vikram; Mounajjed, Taofic; Foo, Wai Chin; Torbenson, Michael S.; Kleiner, David E.; Laird, Peter W.; Wheeler, David A.; Mcree, Autumn J.; Bathe, Oliver F.; Andersen, Jesper B.; Bardeesy, Nabeel; Roberts, Lewis R.; Kwong, Lawrence N.. - In: CELL REPORTS. - ISSN 2211-1247. - 19:13(2017), pp. 2878-2880. [10.1016/j.celrep.2017.06.008]

Erratum: Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles (Cell Reports (2017) 18(11) (2780–2794) (S2211124717302140) (10.1016/j.celrep.2017.02.033))

ALVARO, Domenico;BRAGAZZI, MARIA CONSIGLIA;CARDINALE, VINCENZO;Carpino, Guido;FRANCHITTO, Antonio;GAUDIO, EUGENIO;
2017

Abstract

Cholangiocarcinoma (CCA) is an aggressive malignancy of the bile ducts, with poor prognosis and limited treatment options. Here, we describe the integrated analysis of somatic mutations, RNA expression, copy number, and DNA methylation by The Cancer Genome Atlas, of a set of predominantly intrahepatic CCA cases, and propose a molecular classification scheme. We identified an IDH-mutant enriched subtype with distinct molecular features including low expression of chromatin modifiers, elevated expression of mitochondrial genes, and increased mitochondrial DNA copy number. Leveraging the multi-platform data, we observed that ARID1A exhibited DNA hypermethylation and decreased expression in the IDH-mutant subtype. More broadly, we found that IDH mutations are associated with an expanded histological spectrum of liver tumors with molecular features that stratify with CCA. Our studies reveal insights into the molecular pathogenesis and heterogeneity of cholangiocarcinoma and provide classification information of potential therapeutic significance.
2017
Biochemistry, Genetics and Molecular Biology (all)
01 Pubblicazione su rivista::01a Articolo in rivista
Erratum: Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles (Cell Reports (2017) 18(11) (2780–2794) (S2211124717302140) (10.1016/j.celrep.2017.02.033)) / Farshidfar, Farshad; Zheng, Siyuan; Gingras, Marie Claude; Newton, Yulia; Shih, Juliann; Robertson, A. Gordon; Hinoue, Toshinori; Hoadley, Katherine A.; Gibb, Ewan A.; Roszik, Jason; Covington, Kyle R.; Wu, Chia Chin; Shinbrot, Eve; Stransky, Nicolas; Hegde, Apurva; Yang, Ju Dong; Reznik, Ed; Sadeghi, Sara; Pedamallu, Chandra Sekhar; Ojesina, Akinyemi I.; Hess, Julian M.; Auman, J. Todd; Rhie, Suhn K.; Bowlby, Reanne; Borad, Mitesh J.; Akbani, Rehan; Allotey, Loretta K.; Ally, Adrian; Alvaro, Domenico; Andersen, Jesper B.; Appelbaum, Elizabeth L.; Arora, Arshi; Auman, J. Todd; Balasundaram, Miruna; Balu, Saianand; Bardeesy, Nabeel; Bathe, Oliver F.; Baylin, Stephen B.; Beroukhim, Rameen; Berrios, Mario; Bodenheimer, Tom; Boice, Lori; Bootwalla, Moiz S.; Borad, Mitesh J.; Bowen, Jay; Bowlby, Reanne; Bragazzi, MARIA CONSIGLIA; Brooks, Denise; Cardinale, Vincenzo; Carlsen, Rebecca; Carpino, Guido; Carvalho, Andre L.; Chaiteerakij, Roongruedee; Chandan, Vishal C.; Cherniack, Andrew D.; Chin, Lynda; Cho, Juok; Choe, Gina; Chuah, Eric; Chudamani, Sudha; Cibulskis, Carrie; Cordes, Matthew G.; Covington, Kyle R.; Crain, Daniel; Curley, Erin; De Rose, Agostino Maria; Defreitas, Timothy; Demchok, John A.; Deshpande, Vikram; Dhalla, Noreen; Ding, Li; Evason, Kimberley; Farshidfar, Farshad; Felau, Ina; Ferguson, Martin L.; Foo, Wai Chin; Franchitto, Antonio; Frazer, Scott; Fronick, Catrina C.; Fulton, Lucinda A.; Fulton, Robert S.; Gabriel, Stacey B.; Gardner, Johanna; Gastier Foster, Julie M.; Gaudio, Eugenio; Gehlenborg, Nils; Genovese, Giannicola; Gerken, Mark; Getz, Gad; Giama, Nasra H.; Gibbs, Richard A.; Gingras, Marie Claude; Giuliante, Felice; Grazi, Gian Luca; Hayes, D. Neil; Hegde, Apurva M.; Heiman, David I.; Hess, Julian M.; Hinoue, Toshinori; Hoadley, Katherine A.; Holbrook, Andrea; Holt, Robert A.; Hoyle, Alan P.; Huang, Mei; Hutter, Carolyn M.; Jefferys, Stuart R.; Jones, Steven J. M.; Jones, Corbin D.; Kasaian, Katayoon; Kelley, Robin K.; Kim, Jaegil; Kleiner, David E.; Kocher, Jean Pierre A.; Kwong, Lawrence N.; Lai, Phillip H.; Laird, Peter W.; Lawrence, Michael S.; Leraas, Kristen M.; Lichtenberg, Tara M.; Lin, Pei; Liu, Wenbin; Liu, Jia; Lolla, Laxmi; Lu, Yiling; Ma, Yussanne; Mallery, David; Mardis, Elaine R.; Marra, Marco A.; Matsushita, Marcus M.; Mayo, Michael; Mclellan, Michael D.; Mcree, Autumn J.; Meier, Sam; Meng, Shaowu; Meyerson, Matthew; Mieczkowski, Piotr A.; Miller, Christopher A.; Mills, Gordon B.; Moore, Richard A.; Morris, Scott; Mose, Lisle E.; Moser, Catherine D.; Mounajjed, Taofic; Mungall, Andrew J.; Mungall, Karen; Murray, Bradley A.; Naresh, Rashi; Newton, Yulia; Noble, Michael S.; O'Brien, Daniel R.; Ojesina, Akinyemi I.; Parker, Joel S.; Patel, Tushar C.; Paulauskis, Joseph; Pedamallu, Chandra Sekhar; Penny, Robert; Perou, Charles M.; Perou, Amy H.; Pihl, Todd; Radenbaugh, Amie J.; Ramirez, Nilsa C.; Rathmell, W. Kimryn; Reznik, Ed; Rhie, Suhn K.; Roach, Jeffrey; Roberts, Lewis R.; Robertson, A. Gordon; Sadeghi, Sara; Saksena, Gordon; Sander, Chris; Schein, Jacqueline E.; Schmidt, Heather K.; Schumacher, Steven E.; Shelton, Candace; Shelton, Troy; Shen, Ronglai; Sheth, Margi; Shi, Yan; Shih, Juliann; Shinbrot, Eve; Shroff, Rachna; Simons, Janae V.; Sipahimalani, Payal; Skelly, Tara; Sofia, Heidi J.; Soloway, Matthew G.; Stoppler, Hubert; Stransky, Nicolas; Stuart, Josh; Sun, Qiang; Tam, Angela; Tan, Donghui; Tarnuzzer, Roy; Thiessen, Nina; Thorne, Leigh B.; Torbenson, Michael S.; Van Den Berg, David J.; Veluvolu, Umadevi; Verhaak, Roel G. W.; Voet, Doug; Wan, Yunhu; Wang, Zhining; Weinstein, John N.; Weisenberger, Daniel J.; Wheeler, David A.; Wilson, Richard K.; Wise, Lisa; Wong, Tina; Wu, Chia Chin; Wu, Ye; Xi, Liu; Yang, Ju Dong; Yang, Liming; Zenklusen, Jean C.; Zhang, Hailei; Zhang, Jiashan; Zheng, Siyuan; Zmuda, Erik; Zhu, Andrew X.; Stuart, Josh M.; Sander, Chris; Akbani, Rehan; Cherniack, Andrew D.; Deshpande, Vikram; Mounajjed, Taofic; Foo, Wai Chin; Torbenson, Michael S.; Kleiner, David E.; Laird, Peter W.; Wheeler, David A.; Mcree, Autumn J.; Bathe, Oliver F.; Andersen, Jesper B.; Bardeesy, Nabeel; Roberts, Lewis R.; Kwong, Lawrence N.. - In: CELL REPORTS. - ISSN 2211-1247. - 19:13(2017), pp. 2878-2880. [10.1016/j.celrep.2017.06.008]
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