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

被引：726

作者：

Jusakul, Apinya ^{[1
,2
,3
,4
]}

Cutcutache, Ioana ^{[5
]}

Yong, Chern Han ^{[1
,5
]}

Lim, Jing Quan ^{[2
,6
]}

Huang, Mi Ni ^{[5
]}

Padmanabhan, Nisha ^{[1
]}

Nellore, Vishwa ^{[7
]}

Kongpetch, Sarinya ^{[2
,8
,9
,10
]}

Ng, Alvin Wei Tian ^{[11
]}

Ng, Ley Moy ^{[12
]}

Choo, Su Pin ^{[13
]}

Myint, Swe Swe ^{[2
]}

Thanan, Raynoo ^{[14
]}

Nagarajan, Sanjanaa ^{[2
]}

Lim, Weng Khong ^{[1
,2
]}

Ng, Cedric Chuan Young ^{[2
]}

Boot, Arnoud ^{[1
,5
]}

Liu, Mo ^{[1
,5
]}

Ong, Choon Kiat ^{[6
]}

Rajasegaran, Vikneswari ^{[2
]}

Lie, Stefanus ^{[2
,15
]}

Lim, Alvin Soon Tiong ^{[16
]}

Lim, Tse Hui ^{[16
]}

Tan, Jing ^{[2
]}

Loh, Jia Liang ^{[2
]}

McPherson, John R. ^{[5
]}

Khuntikeo, Narong ^{[8
,9
,17
]}

Bhudhisawasdi, Vajaraphongsa ^{[17
]}

Yongvanit, Puangrat ^{[8
,9
]}

Wongkham, Sopit ^{[14
]}

Totoki, Yasushi ^{[18
]}

Nakamura, Hiromi ^{[18
]}

Arai, Yasuhito ^{[18
]}

Yamasaki, Satoshi ^{[19
]}

Chow, Pierce Kah-Hoe ^{[20
,21
]}

Chung, Alexander Yaw Fui ^{[22
]}

Ooi, London Lucien Peng Jin ^{[22
]}

Lim, Kiat Hon ^{[23
]}

Dima, Simona ^{[24
]}

Duda, Dan G. ^{[25
,26
]}

Popescu, Irinel ^{[24
]}

Broet, Philippe ^{[27
]}

Hsieh, Sen-Yung ^{[28
,29
]}

Yu, Ming-Chin ^{[29
,30
]}

Scarpa, Aldo ^{[31
]}

Lai, Jiaming ^{[32
]}

Luo, Di-Xian ^{[33
]}

Lopes Carvalho, Andre ^{[34
]}

Luiz Vettore, Andre ^{[35
]}

Rhee, Hyungjin ^{[36
]}

机构：

[1] Duke NUS Med Sch, Program Canc & Stem Cell Biol, Singapore, Singapore

[2] Natl Canc Ctr Singapore, Div Med Sci, Lab Canc Epigenome, Singapore, Singapore

[3] Khon Kaen Univ, Ctr Res & Dev, Med Diagnost Labs, Khon Kaen, Thailand

[4] Khon Kaen Univ, Dept Clin Immunol & Transfus Sci, Fac Assoc Med Sci, Khon Kaen, Thailand

[5] Duke NUS Med Sch, Ctr Computat Biol, Singapore, Singapore

[6] Natl Canc Ctr Singapore, Lymphoma Genom Translat Res Lab, Div Med Oncol, Singapore, Singapore

[7] Duke Univ, Ctr Genom & Computat Biol, Dept Biostat & Bioinformat, Durham, NC USA

[8] Khon Kaen Univ, Cholangiocarcinoma Screening & Care Program, Khon Kaen, Thailand

[9] Khon Kaen Univ, Fac Med, Liver Fluke & Cholangiocarcinoma Res Ctr, Khon Kaen, Thailand

[10] Khon Kaen Univ, Fac Med, Dept Pharmacol, Khon Kaen, Thailand

[11] Natl Univ Singapore, NUS Grad Sch Integrat Sci & Engn, Singapore, Singapore

[12] Natl Univ Singapore, Canc Sci Inst Singapore, Singapore, Singapore

[13] Natl Canc Ctr Singapore, Div Med Oncol, Singapore, Singapore

[14] Khon Kaen Univ, Fac Med, Dept Biochem, Khon Kaen, Thailand

[15] Natl Canc Ctr Singapore, Div Radiat Oncol, Singapore, Singapore

[16] Singapore Gen Hosp, Dept Mol Pathol, Cytogenet Lab, Singapore, Singapore

[17] Khon Kaen Univ, Fac Med, Dept Surg, Khon Kaen, Thailand

[18] Natl Canc Ctr, Res Inst, Div Canc Genom, Tokyo, Japan

[19] Univ Tokyo, Inst Med Sci, Human Genome Ctr, Lab Mol Med, Tokyo, Japan

[20] Natl Canc Ctr Singapore, Div Surg Oncol, Singapore, Singapore

[21] Duke NUS Med Sch, Off Clin Sci, Singapore, Singapore

[22] Singapore Gen Hosp, Dept Hepatopancreatobiliary Transplant Surg, Singapore, Singapore

[23] Singapore Gen Hosp, Dept Anat Pathol, Singapore, Singapore

[24] Fundeni Clin Inst, Ctr Digest Dis & Liver Transplantat, Bucharest, Romania

[25] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Labs Tumor Biol, Boston, MA 02114 USA

[26] Harvard Med Sch, Boston, MA USA

[27] DHU Hepatinov, Hop Paul Brousse, AP HP, Villejuif, France

[28] Chang Gung Mem Hosp, Dept Gastroenterol & Hepatol, Taoyuan, Taiwan

[29] Chang Gung Univ, Taoyuan, Taiwan

[30] Chang Gung Mem Hosp, Dept Gen Surg, Taoyuan, Taiwan

[31] Univ & Hosp Trust Verona, Appl Res Canc Ctr ARC Net, Verona, Italy

[32] Sun Yat Sen Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Guangzhou, Guangdong, Peoples R China

[33] Southern Med Univ, Peoples Hosp Chenzhou 1, Natl & Local Joint Engn Lab High Through Mol Diag, Chenzhou, Peoples R China

[34] Barretos Canc Hosp, Sao Paulo, Brazil

[35] Univ Fed Sao Paulo, Dept Biol Sci, Lab Canc Mol Biol, Rua Pedro Toledo, Sao Paulo, Brazil

[36] Yonsei Univ, Brain Korea PLUS Project Med Sci 21, Integrated Genom Res Ctr Metab Regulat, Dept Pathol,Coll Med, Seoul, South Korea

[37] Los Alamos Natl Lab, Theoret Biol & Biophys T 6, Los Alamos, NM USA

[38] Los Alamos Natl Lab, Ctr Nonlinear Studies, Los Alamos, NM USA

[39] Duke Univ, Dept Comp Sci, Durham, NC USA

[40] Natl Heart Ctr, SingHlth Duke NUS Inst Precis Med, Singapore, Singapore

[41] Khon Kaen Univ, Fac Med, Dept Pathol, Khon Kaen, Thailand

[42] Inst Mol & Cell Biol, Singapore, Singapore

[43] Genome Inst Singapore, Singapore, Singapore

来源：

CANCER DISCOVERY | 2017年 / 7卷 / 10期

基金：

中国国家自然科学基金; 英国医学研究理事会; 新加坡国家研究基金会;

关键词：

BILIARY-TRACT CANCER; SEQUENCING DATA; COPY NUMBER; INTRAHEPATIC CHOLANGIOCARCINOMAS; RECURRENT MUTATIONS; SOMATIC MUTATIONS; GENE FUSIONS; TUMOR TYPES; EXPRESSION; IDENTIFICATION;

D O I：

10.1158/2159-8290.CD-17-0368

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：1116 / 1135

页数：20

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