Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma
Year: 2017
Type: article
Study design: Observational Study
Abstract: Cholangiocarcinoma (CCA) is a hepatobiliary malignancy exhibiting high incidence in countries with endemic liver-fluke infection. We analyzed 489 CCAs from 10 countries, combining whole-genome (71 cases), targeted/exome, copy-number, gene expression, and DNA methylation information. Integrative clustering defined 4 CCA clusters—fluke-positive CCAs (clusters 1/2) are enriched in ERBB2 amplifications and TP53 mutations; conversely, fluke-negative CCAs (clusters 3/4) exhibit high copy-number alterations and PD-1/PD-L2 expression, or epigenetic mutations (IDH1/2, BAP1) and FGFR/PRKA-related gene rearrangements. Whole-genome analysis highlighted FGFR2 3′ untranslated region deletion as a mechanism of FGFR2 upregulation. Integration of noncoding promoter mutations with protein–DNA binding profiles demonstrates pervasive modulation of H3K27me3-associated sites in CCA. Clusters 1 and 4 exhibit distinct DNA hypermethylation patterns targeting either CpG islands or shores—mutation signature and subclonality analysis suggests that these reflect different mutational pathways. Our results exemplify how genetics, epigenetics, and environmental carcinogens can interplay across different geographies to generate distinct molecular subtypes of cancer. Significance: Integrated whole-genome and epigenomic analysis of CCA on an international scale identifies new CCA driver genes, noncoding promoter mutations, and structural variants. CCA molecular landscapes differ radically by etiology, underscoring how distinct cancer subtypes in the same organ may arise through different extrinsic and intrinsic carcinogenic processes. Cancer Discov; 7(10); 1116–35. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 1047
Source: Cancer Discovery
Authors: Apinya Jusakul, Ioana Cutcutache, Chern Han Yong, Jing Quan Lim, Mi Ni Huang, Nisha Padmanabhan, Vishwa Nellore, Sarinya Kongpetch, Alvin Wei Tian Ng, Ley Moy Ng, Su Pin Choo, Swe Swe Myint, Raynoo Thanan, Sanjanaa Nagarajan, Weng Khong Lim, Cedric Chuan Young Ng, Arnoud Boot, Mo Liu, Choon Kiat Ong, Vikneswari Rajasegaran, Stefanus Lie, Alvin Soon Tiong Lim, Tse Hui Lim, Jing Tan, Jia Liang Loh, John R. McPherson, Narong Khuntikeo, Vajaraphongsa Bhudhisawasdi, Puangrat Yongvanit, Sopit Wongkham, Yasushi Totoki, Hiromi Nakamura, Yasuhito Arai, Satoshi Yamasaki, Pierce Kah-Hoe Chow, Alexander Yaw Fui Chung, London Lucien Peng Jin Ooi, Kiat Hon Lim, Simona Dima, Dan G. Duda, Irinel Popescu, Philippe Broet, Sen-Yung Hsieh, Ming-Chin Yu, Aldo Scarpa, Jiaming Lai, Di-Xian Luo, André Lopes Carvalho, André Luiz Vettore, Hyungjin Rhee, Young Nyun Park, Ludmil B. Alexandrov, Raluca Gordân, Steven G. Rozen, Tatsuhiro Shibata, Chawalit Pairojkul, Bin Tean Teh, Patrick Tan
Institutions: Khon Kaen University, Duke-NUS Medical School, National Cancer Centre Singapore, Duke University, National University of Singapore, Singapore General Hospital, National Cancer Centre Japan, The University of Tokyo, Institutul Clinic Fundeni, Harvard University, Massachusetts General Hospital, Assistance Publique – Hôpitaux de Paris, Hôpital Paul-Brousse, Chang Gung University, Chang Gung Memorial Hospital, Taoyuan Chang Gung Memorial Hospital, Linkou Chang Gung Memorial Hospital, University of Verona, The First Affiliated Hospital, Sun Yat-sen University, Chenzhou First People's Hospital, Southern Medical University, Hospital de Câncer de Barretos, Universidade Federal de São Paulo, Yonsei University, Yonsei University Health System, Los Alamos National Laboratory, SingHealth Duke-NUS Academic Medical Centre, National Heart Centre Singapore, Institute of Molecular and Cell Biology, Genome Institute of Singapore
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Japan Agency for Medical Research and Development, Duke-NUS Medical School, Fondazione Italiana per la ricerca sulle Malattie del Pancreas, National Research Foundation, National University of Singapore, National Research Foundation Singapore, Singapore General Hospital, National Natural Science Foundation of China, Associazione Italiana per la Ricerca sul Cancro, Genome Institute of Singapore, National Institutes of Health, Medical Research Council, National Medical Research Council, National Cancer Institute
OpenAlex ID: W2724543993