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Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles

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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 (Julia), 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.·2017·Cell Reports

DOI 10.1016/j.celrep.2017.02.033

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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.

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Authors: Farshidfar, F., Zheng, S., Gingras, M.-C., Newton, Y., Shih, J., Robertson, A. G., Hinoue, T., Hoadley, K. A., Gibb, E. A., Roszik, J., Covington, K. R., Wu, C.-C., Shinbrot, E., Stransky, N., Hegde, A., Yang, J. D., Reznik, E., Sadeghi, S., Pedamallu, C. S., Ojesina, A. I., Hess, J. M., Auman, J. T., Rhie, S. K., Bowlby, R., Borad, M. J., Akbani, R., Allotey, L. K., Ally, A., Alvaro, D., Andersen, J. B., Appelbaum, E. L., Arora, A., Auman, J. T., Balasundaram, M., Balu, S., Bardeesy, N., Bathe, O. F., Baylin, S. B., Beroukhim, R., Berrios, M., Bodenheimer, T., Boice, L., Bootwalla, M. S., Borad, M. J., Bowen, J., Bowlby, R., Bragazzi, M. C., Brooks, D., Cardinale, V., Carlsen, R., Carpino, G., Carvalho, A. L., Chaiteerakij, R., Chandan, V. C., Cherniack, A. D., Chin, L., Cho, J., Choe, G., Chuah, E., Chudamani, S., Cibulskis, C., Cordes, M. G., Covington, K. R., Crain, D., Curley, E., De Rose, A. M., Defreitas, T., Demchok, J. A., Deshpande, V., Dhalla, N., Ding, L., Evason, K., Farshidfar, F., Felau, I., Ferguson, M. L., Foo, W. C., Franchitto, A., Frazer, S., Fronick, C. C., Fulton, L. A., Fulton, R. S., Gabriel, S. B., Gardner, J., Gastier-Foster, J. M., Gaudio, E., Gehlenborg, N., Genovese, G., Gerken, M., Getz, G., Giama, N. H., Gibbs, R. A., Gingras, M.-C., Giuliante, F., Grazi, G. L., Hayes, D. N., Hegde, A. M., Heiman, D. I., Hess, J. M., Hinoue, T., Hoadley, K. A., Holbrook, A., Holt, R. A., Hoyle, A. P., Huang, M., Hutter, C. M., Jefferys, S. R., Jones, S. J. M., Jones, C. D., Kasaian, K., Kelley, R. K., Kim, J., Kleiner, D. E., Kocher, J.-P. A., Kwong, L. N., Lai, P. H., Laird, P. W., Lawrence, M. S., Leraas, K. M., Lichtenberg, T. M., Lin, P., Liu, W., Liu, J., Lolla, L., Lu, Y., Ma, Y., Mallery, D., Mardis, E. R., Marra, M. A., Matsushita, M. M., Mayo, M., McLellan, M. D., McRee, A. J., Meier, S., Meng, S., Meyerson, M., Mieczkowski, P. A., Miller, C. A., Mills, G. B., Moore, R. A., Morris, S., Mose, L. E., Moser, C. D., Mounajjed, T., Mungall, A. J., Mungall, K., Murray, B. A., Naresh, R., Newton, Y., Noble, M. S., O’Brien, D. R., Ojesina, A. I., Parker, J. S., Patel, T. C., Paulauskis, J., Pedamallu, C. S., Penny, R., Perou, C. M., Perou, A. H., Pihl, T., Radenbaugh, A. J., Ramirez, N. C., Rathmell, W. K., Reznik, E., Rhie, S. K., Roach, J., Roberts, L. R., Robertson, A. G., Sadeghi, S., Saksena, G., Sander, C., Schein, J. E., Schmidt, H. K., Schumacher, S. E., Shelton, C., Shelton, T., Shen, R., Sheth, M., Shi, Y., Shih, J., Shinbrot, E., Shroff, R., Simons, J. V., Sipahimalani, P., Skelly, T., Sofia, H. J., Soloway, M. G., Stoppler, H., Stransky, N., Stuart, J., Sun, Q., Tam, A., Tan, D., Tarnuzzer, R., Thiessen, N., Thorne, L. B., Torbenson, M. S., Van Den Berg, D. J., Veluvolu, U., Verhaak, R. G. W., Voet, D., Wan, Y., Wang, Z., Weinstein, J. N., Weisenberger, D. J., Wheeler, D. A., Wilson, R. K., Wise, L., Wong, T., Wu, C.-C., Wu, Y., Xi, L., Yang, J. D., Yang, L., Zenklusen, J. C., Zhang, H., Zhang, J. (., Zheng, S., Zmuda, E., Zhu, A. X., Stuart, J. M., Sander, C., Akbani, R., Cherniack, A. D., Deshpande, V., Mounajjed, T., Foo, W. C., Torbenson, M. S., Kleiner, D. E., Laird, P. W., Wheeler, D. A., McRee, A. J., Bathe, O. F., Andersen, J. B., Bardeesy, N., Roberts, L. R., & Kwong, L. N.
Venue: Cell Reports
Publisher: Elsevier BV
Published: 2017-03
Volume: 18
Issue: 11
Pages: 2780-2794
ISSN: 2211-1247 (ISSN-L)
DOI: 10.1016/j.celrep.2017.02.033
OpenAlex: W2603204749
Cited by: 610
References: 8
FWCI: 58.12
Type: journal article
Language: en
Open access: gold

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Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles

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