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

 Apinya Jusakul  ;  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 Young 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 Peng Jin 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  ;  André 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  ;  Patrick Tan 
 CANCER DISCOVERY, Vol.7(10) : 1116-1135, 2017 
Journal Title
Issue Date
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.
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1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Radiology (영상의학교실) > 1. Journal Papers
Yonsei Authors
Park, Young Nyun(박영년) ORCID logo https://orcid.org/0000-0003-0357-7967
Rhee, Hyungjin(이형진) ORCID logo https://orcid.org/0000-0001-7759-4458
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