Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles. 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., 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. Cell Rep, 18(11):2780-2794, 2017. 2211-1247 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 Cancer Genome Atlas Network 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 P30 CA016672/CA/NCI NIH HHS/United States U24 CA143882/CA/NCI NIH HHS/United States U54 HG003067/HG/NHGRI NIH HHS/United States U54 HG006097/HG/NHGRI NIH HHS/United States R01 GM109031/GM/NIGMS NIH HHS/United States U24 CA210950/CA/NCI NIH HHS/United States U24 CA143845/CA/NCI NIH HHS/United States U24 CA143799/CA/NCI NIH HHS/United States U54 HG003273/HG/NHGRI NIH HHS/United States U24 CA144025/CA/NCI NIH HHS/United States U24 CA143840/CA/NCI NIH HHS/United States U24 CA143843/CA/NCI NIH HHS/United States U24 CA143858/CA/NCI NIH HHS/United States U24 CA143848/CA/NCI NIH HHS/United States U54 HG003079/HG/NHGRI NIH HHS/United States R01 CA180778/CA/NCI NIH HHS/United States U24 CA210949/CA/NCI NIH HHS/United States U24 CA143883/CA/NCI NIH HHS/United States U24 CA143867/CA/NCI NIH HHS/United States U24 CA199461/CA/NCI NIH HHS/United States U24 CA210990/CA/NCI NIH HHS/United States Journal Article United States 2017/03/16 Cell Rep. 2017 Mar 14;18(11):2780-2794. doi: 10.1016/j.celrep.2017.02.033.
doi  abstract   bibtex   
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.
@article{RN6112,
   author = {Farshidfar, F. and Zheng, S. and Gingras, M. C. and Newton, Y. and Shih, J. and Robertson, A. G. and Hinoue, T. and Hoadley, K. A. and Gibb, E. A. and Roszik, J. and Covington, K. R. and Wu, C. C. and Shinbrot, E. and Stransky, N. and Hegde, A. and Yang, J. D. and Reznik, E. and Sadeghi, S. and Pedamallu, C. S. and Ojesina, A. I. and Hess, J. M. and Auman, J. T. and Rhie, S. K. and Bowlby, R. and Borad, M. J. and Zhu, A. X. and Stuart, J. M. and Sander, C. and Akbani, R. and Cherniack, A. D. and Deshpande, V. and Mounajjed, T. and Foo, W. C. and Torbenson, M. S. and Kleiner, D. E. and Laird, P. W. and Wheeler, D. A. and McRee, A. J. and Bathe, O. F. and Andersen, J. B. and Bardeesy, N. and Roberts, L. R. and Kwong, L. N.},
   title = {Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles},
   journal = {Cell Rep},
   volume = {18},
   number = {11},
   pages = {2780-2794},
   note = {2211-1247
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
Cancer Genome Atlas Network
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
P30 CA016672/CA/NCI NIH HHS/United States
U24 CA143882/CA/NCI NIH HHS/United States
U54 HG003067/HG/NHGRI NIH HHS/United States
U54 HG006097/HG/NHGRI NIH HHS/United States
R01 GM109031/GM/NIGMS NIH HHS/United States
U24 CA210950/CA/NCI NIH HHS/United States
U24 CA143845/CA/NCI NIH HHS/United States
U24 CA143799/CA/NCI NIH HHS/United States
U54 HG003273/HG/NHGRI NIH HHS/United States
U24 CA144025/CA/NCI NIH HHS/United States
U24 CA143840/CA/NCI NIH HHS/United States
U24 CA143843/CA/NCI NIH HHS/United States
U24 CA143858/CA/NCI NIH HHS/United States
U24 CA143848/CA/NCI NIH HHS/United States
U54 HG003079/HG/NHGRI NIH HHS/United States
R01 CA180778/CA/NCI NIH HHS/United States
U24 CA210949/CA/NCI NIH HHS/United States
U24 CA143883/CA/NCI NIH HHS/United States
U24 CA143867/CA/NCI NIH HHS/United States
U24 CA199461/CA/NCI NIH HHS/United States
U24 CA210990/CA/NCI NIH HHS/United States
Journal Article
United States
2017/03/16
Cell Rep. 2017 Mar 14;18(11):2780-2794. doi: 10.1016/j.celrep.2017.02.033.},
   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.},
   keywords = {Adult
Aged
Aged, 80 and over
Bile Duct Neoplasms/enzymology/*genetics
Cholangiocarcinoma/enzymology/*genetics
Chromatin/metabolism
DNA Methylation/genetics
DNA-Binding Proteins
Female
Gene Expression Regulation, Neoplastic
Genomics/*methods
Humans
Isocitrate Dehydrogenase/*genetics
Liver/pathology
Liver Neoplasms/genetics/pathology
Male
Middle Aged
Mitochondria/metabolism
Mutation/*genetics
Nuclear Proteins/genetics
Pancreatic Neoplasms/genetics/pathology
Promoter Regions, Genetic/genetics
RNA, Long Noncoding/genetics/metabolism
RNA, Messenger/genetics/metabolism
Transcription Factors/genetics
Arid1a
DNA methylation
Idh
RNA sequencing
Tcga
cholangiocarcinoma
integrative genomics
lncRNAs
multi-omics
whole exome},
   DOI = {10.1016/j.celrep.2017.02.033},
   year = {2017},
   type = {Journal Article}
}

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