| Literature DB >> 28667006 |
Apinya Jusakul1,2,3, Ioana Cutcutache4, Chern Han Yong1,4, Jing Quan Lim2,5, Mi Ni Huang4, Nisha Padmanabhan1, Vishwa Nellore6, Sarinya Kongpetch2,7,8, Alvin Wei Tian Ng9, Ley Moy Ng10, Su Pin Choo11, Swe Swe Myint2, Raynoo Thanan12, Sanjanaa Nagarajan2, Weng Khong Lim1,2, Cedric Chuan Young Ng2, Arnoud Boot1,4, Mo Liu1,4, Choon Kiat Ong5, Vikneswari Rajasegaran2, Stefanus Lie2,13, Alvin Soon Tiong Lim14, Tse Hui Lim14, Jing Tan2, Jia Liang Loh2, John R McPherson4, Narong Khuntikeo7,15, Vajaraphongsa Bhudhisawasdi15, Puangrat Yongvanit7, Sopit Wongkham12, Yasushi Totoki16, Hiromi Nakamura16, Yasuhito Arai16, Satoshi Yamasaki17, Pierce Kah-Hoe Chow18, Alexander Yaw Fui Chung19, London Lucien Peng Jin Ooi19, Kiat Hon Lim20, Simona Dima21, Dan G Duda22, Irinel Popescu21, Philippe Broet23, Sen-Yung Hsieh24, Ming-Chin Yu25, Aldo Scarpa26, Jiaming Lai27, Di-Xian Luo28, André Lopes Carvalho29, André Luiz Vettore30, Hyungjin Rhee31, Young Nyun Park31, Ludmil B Alexandrov32, Raluca Gordân33,34, Steven G Rozen35,4,36, Tatsuhiro Shibata37,17, Chawalit Pairojkul38, Bin Tean Teh35,2,10,36,39, Patrick Tan35,10,36,40.
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. ©2017 American Association for Cancer Research.Entities:
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Year: 2017 PMID： 28667006 PMCID： PMC5628134 DOI： 10.1158/2159-8290.CD-17-0368
Source DB: PubMed Journal: Cancer Discov ISSN： 2159-8274 Impact factor: 39.397