Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma.

TitleWhole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma.
Publication TypeJournal Article
Year of Publication2017
AuthorsJusakul, Apinya, 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 Youn 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 Pen 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, Andre 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, and Patrick Tan
JournalCancer Discov
Volume7
Issue10
Pagination1116-1135
Date Published2017 10
ISSN2159-8290
KeywordsBile Duct Neoplasms, Cholangiocarcinoma, CpG Islands, DNA Methylation, Epigenomics, Gene Expression Regulation, Neoplastic, Gene Regulatory Networks, Genome-Wide Association Study, Humans, Receptor, ErbB-2, Receptor, Fibroblast Growth Factor, Type 2, Tumor Suppressor Protein p53
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 amplifications and mutations; conversely, fluke-negative CCAs (clusters 3/4) exhibit high copy-number alterations and / expression, or epigenetic mutations () and /-related gene rearrangements. Whole-genome analysis highlighted 3' untranslated region deletion as a mechanism of 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. 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. .

DOI10.1158/2159-8290.CD-17-0368
Alternate JournalCancer Discov
Original PublicationWhole-genome and epigenomic landscapes of etiologically distinct subtypes of cholangiocarcinoma.
PubMed ID28667006
PubMed Central IDPMC5628134
Grant ListP01 CA142538 / CA / NCI NIH HHS / United States
S10 OD018164 / OD / NIH HHS / United States