%0 Journal Article %J Cell Rep %D 2018 %T Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas. %A Campbell, Joshua D %A Yau, Christina %A Bowlby, Reanne %A Liu, Yuexin %A Brennan, Kevin %A Fan, Huihui %A Taylor, Alison M %A Wang, Chen %A Walter, Vonn %A Akbani, Rehan %A Byers, Lauren Averett %A Creighton, Chad J %A Coarfa, Cristian %A Shih, Juliann %A Cherniack, Andrew D %A Gevaert, Olivier %A Prunello, Marcos %A Shen, Hui %A Anur, Pavana %A Chen, Jianhong %A Cheng, Hui %A Hayes, D Neil %A Bullman, Susan %A Pedamallu, Chandra Sekhar %A Ojesina, Akinyemi I %A Sadeghi, Sara %A Mungall, Karen L %A Robertson, A Gordon %A Benz, Christopher %A Schultz, Andre %A Kanchi, Rupa S %A Gay, Carl M %A Hegde, Apurva %A Diao, Lixia %A Wang, Jing %A Ma, Wencai %A Sumazin, Pavel %A Chiu, Hua-Sheng %A Chen, Ting-Wen %A Gunaratne, Preethi %A Donehower, Larry %A Rader, Janet S %A Zuna, Rosemary %A Al-Ahmadie, Hikmat %A Lazar, Alexander J %A Flores, Elsa R %A Tsai, Kenneth Y %A Zhou, Jane H %A Rustgi, Anil K %A Drill, Esther %A Shen, Ronglei %A Wong, Christopher K %A Stuart, Joshua M %A Laird, Peter W %A Hoadley, Katherine A %A Weinstein, John N %A Peto, Myron %A Pickering, Curtis R %A Chen, Zhong %A Van Waes, Carter %K Carcinoma, Squamous Cell %K Cell Line, Tumor %K DNA Methylation %K Epithelial-Mesenchymal Transition %K Gene Expression Regulation, Neoplastic %K Genomics %K Humans %K Metabolic Networks and Pathways %K Polymorphism, Genetic %X

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smoking and/or human papillomavirus (HPV). SCCs harbor 3q, 5p, and other recurrent chromosomal copy-number alterations (CNAs), DNA mutations, and/or aberrant methylation of genes and microRNAs, which are correlated with the expression of multi-gene programs linked to squamous cell stemness, epithelial-to-mesenchymal differentiation, growth, genomic integrity, oxidative damage, death, and inflammation. Low-CNA SCCs tended to be HPV(+) and display hypermethylation with repression of TET1 demethylase and FANCF, previously linked to predisposition to SCC, or harbor mutations affecting CASP8, RAS-MAPK pathways, chromatin modifiers, and immunoregulatory molecules. We uncovered hypomethylation of the alternative promoter that drives expression of the ΔNp63 oncogene and embedded miR944. Co-expression of immune checkpoint, T-regulatory, and Myeloid suppressor cells signatures may explain reduced efficacy of immune therapy. These findings support possibilities for molecular classification and therapeutic approaches.

%B Cell Rep %V 23 %P 194-212.e6 %8 2018 Apr 03 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/29617660?dopt=Abstract %R 10.1016/j.celrep.2018.03.063 %0 Journal Article %J Cell Rep %D 2017 %T Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles. %A Farshidfar, Farshad %A Zheng, Siyuan %A Gingras, Marie-Claude %A Newton, Yulia %A Shih, Juliann %A Robertson, A Gordon %A Hinoue, Toshinori %A Hoadley, Katherine A %A Gibb, Ewan A %A Roszik, Jason %A Covington, Kyle R %A Wu, Chia-Chin %A Shinbrot, Eve %A Stransky, Nicolas %A Hegde, Apurva %A Yang, Ju Dong %A Reznik, Ed %A Sadeghi, Sara %A Pedamallu, Chandra Sekhar %A Ojesina, Akinyemi I %A Hess, Julian M %A Auman, J Todd %A Rhie, Suhn K %A Bowlby, Reanne %A Borad, Mitesh J %A Zhu, Andrew X %A Stuart, Josh M %A Sander, Chris %A Akbani, Rehan %A Cherniack, Andrew D %A Deshpande, Vikram %A Mounajjed, Taofic %A Foo, Wai Chin %A Torbenson, Michael S %A Kleiner, David E %A Laird, Peter W %A Wheeler, David A %A McRee, Autumn J %A Bathe, Oliver F %A Andersen, Jesper B %A Bardeesy, Nabeel %A Roberts, Lewis R %A Kwong, Lawrence N %K Adult %K Aged %K Aged, 80 and over %K Bile Duct Neoplasms %K Cholangiocarcinoma %K Chromatin %K DNA Methylation %K DNA-Binding Proteins %K Female %K Gene Expression Regulation, Neoplastic %K Genomics %K Humans %K Isocitrate Dehydrogenase %K Liver %K Liver Neoplasms %K Male %K Middle Aged %K Mitochondria %K Mutation %K Nuclear Proteins %K Pancreatic Neoplasms %K Promoter Regions, Genetic %K RNA, Long Noncoding %K RNA, Messenger %K Transcription Factors %X

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.

%B Cell Rep %V 18 %P 2780-2794 %8 2017 Mar 14 %G eng %N 11 %1 https://www.ncbi.nlm.nih.gov/pubmed/28297679?dopt=Abstract %R 10.1016/j.celrep.2017.02.033