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

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

Author Jusakul, Apinya Google Scholar
Cutcutache, Ioana Google Scholar
Yong, Chern Han Google Scholar
Lim, Jing Quan Google Scholar
Huang, Mi Ni Google Scholar
Padmanabhan, Nisha Google Scholar
Nellore, Vishwa Google Scholar
Kongpetch, Sarinya Google Scholar
Ng, Alvin Wei Tian Google Scholar
Ng, Ley Moy Google Scholar
Choo, Su Pin Google Scholar
Myint, Swe Swe Google Scholar
Thanan, Raynoo Google Scholar
Nagarajan, Sanjanaa Google Scholar
Lim, Weng Khong Google Scholar
Ng, Cedric Chuan Young Google Scholar
Boot, Arnoud Google Scholar
Liu, Mo Google Scholar
Ong, Choon Kiat Google Scholar
Rajasegaran, Vikneswari Google Scholar
Lie, Stefanus Google Scholar
Lim, Alvin Soon Tiong Google Scholar
Lim, Tse Hui Google Scholar
Tan, Jing Google Scholar
Loh, Jia Liang Google Scholar
McPherson, John R. Google Scholar
Khuntikeo, Narong Google Scholar
Bhudhisawasdi, Vajaraphongsa Google Scholar
Yongvanit, Puangrat Google Scholar
Wongkham, Sopit Google Scholar
Totoki, Yasushi Google Scholar
Nakamura, Hiromi Google Scholar
Arai, Yasuhito Google Scholar
Yamasaki, Satoshi Google Scholar
Chow, Pierce Kah-Hoe Google Scholar
Chung, Alexander Yaw Fui Google Scholar
Ooi, London Lucien Peng Jin Google Scholar
Lim, Kiat Hon Google Scholar
Dima, Simona Google Scholar
Duda, Dan G. Google Scholar
Popescu, Irinel Google Scholar
Broet, Philippe Google Scholar
Hsieh, Sen-Yung Google Scholar
Yu, Ming-Chin Google Scholar
Scarpa, Aldo Google Scholar
Lai, Jiaming Google Scholar
Luo, Di-Xian Google Scholar
Lopes Carvalho, Andre Google Scholar
Luiz Vettore, Andre Autor UNIFESP Google Scholar
Rhee, Hyungjin Google Scholar
Park, Young Nyun Google Scholar
Alexandrov, Ludmil B. Google Scholar
Gordan, Raluca Google Scholar
Rozen, Steven G. Google Scholar
Shibata, Tatsuhiro Google Scholar
Pairojkul, Chawalit Google Scholar
Teh, Bin Tean Google Scholar
Tan, Patrick Google Scholar
Abstract Cholangiocarcinoma (CCA) is a hepatobiliary malignancy exhibiting high incidence in countries with endemic liver-fl uke 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 defi ned 4 CCA clusters-fl uke-positive CCAs (clusters 1/2) are enriched in ERBB2 amplifi cations and TP53 mutations

conversely, fl uke-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 profi les 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 refl ect 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 identifi es 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. (C) 2017 AACR.
xmlui.dri2xhtml.METS-1.0.item-coverage Philadelphia
Language English
Sponsor Singapore National Medical Research Council
Genome Institute of Singapore
Duke-NUS Medical School
National University of Singapore
National Research Foundation Singapore
Singapore Ministry of Education under the Research Centres of Excellence initiative
National University Cancer Institute, Singapore (NCIS) Centre Grant
Japan Agency for Medical Research and Development (Practical Research for Innovative Cancer Control)
National Cancer Center Research and Development Funds
Italian Cancer Genome Project
Associazione Italiana Ricerca sul Cancro
Italian Ministry of University Health
NCI of the NIH
National Natural Science Foundation of China
Date 2017
Published in Cancer Discovery. Philadelphia, v. 7, n. 10, p. 1116-1135, 2017.
ISSN 2159-8274 (Sherpa/Romeo, impact factor)
Publisher Amer Assoc Cancer Research
Extent 1116-1135
Origin http://dx.doi.org/10.1158/2159-8290.CD-17-0368
Access rights Closed access
Type Article
Web of Science ID WOS:000412219800017
URI https://repositorio.unifesp.br/handle/11600/57261

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