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Cancer Discov. 2017 Oct;7(10):1116-1135. doi: 10.1158/2159-8290.CD-17-0368. Epub 2017 Jun 30.

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

Author information

1
Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore.
2
Laboratory of Cancer Epigenome, Division of Medical Science, National Cancer Centre Singapore, Singapore.
3
The Centre for Research and Development of Medical Diagnostic Laboratories and Department of Clinical Immunology and Transfusion Sciences, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand.
4
Centre for Computational Biology, Duke-NUS Medical School, Singapore.
5
Lymphoma Genomic Translational Research Laboratory, National Cancer Centre Singapore, Division of Medical Oncology, Singapore.
6
Department of Biostatistics and Bioinformatics, Center for Genomic and Computational Biology, Duke University, Durham, North Carolina.
7
Cholangiocarcinoma Screening and Care Program and Liver Fluke and Cholangiocarcinoma Research Centre, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
8
Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
9
NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore.
10
Cancer Science Institute of Singapore, National University of Singapore, Singapore.
11
Division of Medical Oncology, National Cancer Centre Singapore, Singapore.
12
Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
13
Division of Radiation Oncology, National Cancer Centre Singapore, Singapore.
14
Cytogenetics Laboratory, Department of Molecular Pathology, Singapore General Hospital, Singapore.
15
Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
16
Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
17
Laboratory of Molecular Medicine, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Japan.
18
Division of Surgical Oncology, National Cancer Center Singapore and Office of Clinical Sciences, Duke-NUS Medical School, Singapore.
19
Department of Hepatopancreatobiliary/Transplant Surgery, Singapore General Hospital, Singapore.
20
Department of Anatomical Pathology, Singapore General Hospital, Singapore.
21
Center of Digestive Diseases and Liver Transplantation, Fundeni Clinical Institute, Bucharest, Romania.
22
Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
23
DHU Hepatinov, Hôpital Paul Brousse, AP-HP, Villejuif, France.
24
Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.
25
Department of General Surgery, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.
26
Applied Research on Cancer Centre (ARC-Net), University and Hospital Trust of Verona, Verona, Italy.
27
Department of Hepatobiliary Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, P. R. China.
28
National and Local Joint Engineering Laboratory of High-through Molecular Diagnostic Technology, the First People's Hospital of Chenzhou, Southern Medical University, Chenzhou, P. R. China.
29
Barretos Cancer Hospital, Barretos, São Paulo, Brazil.
30
Laboratory of Cancer Molecular Biology, Department of Biological Sciences, Federal University of São Paulo, Rua Pedro de Toledo, São Paulo, Brazil.
31
Department of Pathology, Brain Korea 21 PLUS Project for Medical Science, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Korea.
32
Theoretical Biology and Biophysics (T-6), Los Alamos National Laboratory, and Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico.
33
Department of Biostatistics and Bioinformatics, Center for Genomic and Computational Biology, Duke University, Durham, North Carolina. gmstanp@duke-nus.edu.sg teh.bin.tean@singhealth.com.sg chawalit-pjk2011@hotmail.com tashibat@ncc.go.jp steve.rozen@duke-nus.edu.sg raluca.gordan@duke.edu.
34
Department of Computer Science, Duke University, Durham, North Carolina.
35
Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore. gmstanp@duke-nus.edu.sg teh.bin.tean@singhealth.com.sg chawalit-pjk2011@hotmail.com tashibat@ncc.go.jp steve.rozen@duke-nus.edu.sg raluca.gordan@duke.edu.
36
SingHealth/Duke-NUS Institute of Precision Medicine, National Heart Centre, Singapore.
37
Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan. gmstanp@duke-nus.edu.sg teh.bin.tean@singhealth.com.sg chawalit-pjk2011@hotmail.com tashibat@ncc.go.jp steve.rozen@duke-nus.edu.sg raluca.gordan@duke.edu.
38
Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand. gmstanp@duke-nus.edu.sg teh.bin.tean@singhealth.com.sg chawalit-pjk2011@hotmail.com tashibat@ncc.go.jp steve.rozen@duke-nus.edu.sg raluca.gordan@duke.edu.
39
Institute of Molecular and Cell Biology, Singapore.
40
Genome Institute of Singapore, Singapore.

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.

PMID:
28667006
PMCID:
PMC5628134
DOI:
10.1158/2159-8290.CD-17-0368
[Indexed for MEDLINE]
Free PMC Article

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