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

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.

SUBMITTER: Jusakul A

PROVIDER: S-EPMC5628134 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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

Jusakul Apinya A Cutcutache Ioana I Yong Chern Han CH Lim Jing Quan JQ Huang Mi Ni MN Padmanabhan Nisha N Nellore Vishwa V Kongpetch Sarinya S Ng Alvin Wei Tian AWT Ng Ley Moy LM Choo Su Pin SP Myint Swe Swe SS Thanan Raynoo R Nagarajan Sanjanaa S Lim Weng Khong WK Ng Cedric Chuan Young CCY Boot Arnoud A Liu Mo M Ong Choon Kiat CK Rajasegaran Vikneswari V Lie Stefanus S Lim Alvin Soon Tiong AST Lim Tse Hui TH Tan Jing J Loh Jia Liang JL McPherson John R JR Khuntikeo Narong N Bhudhisawasdi Vajaraphongsa V Yongvanit Puangrat P Wongkham Sopit S Totoki Yasushi Y Nakamura Hiromi H Arai Yasuhito Y Yamasaki Satoshi S Chow Pierce Kah-Hoe PK Chung Alexander Yaw Fui AYF Ooi London Lucien Peng Jin LLPJ Lim Kiat Hon KH Dima Simona S Duda Dan G DG Popescu Irinel I Broet Philippe P Hsieh Sen-Yung SY Yu Ming-Chin MC Scarpa Aldo A Lai Jiaming J Luo Di-Xian DX Carvalho André Lopes AL Vettore André Luiz AL Rhee Hyungjin H Park Young Nyun YN Alexandrov Ludmil B LB Gordân Raluca R Rozen Steven G SG Shibata Tatsuhiro T Pairojkul Chawalit C Teh Bin Tean BT Tan Patrick P

Cancer discovery 20170630 10

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 <i>ERBB2</i> amplifications and <i>TP53</i> mutations; conversely, fluke-negative CCAs (clusters 3/4) exhibit high copy ...[more]

PMID: 28667006

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Dataset Information

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

Publications

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

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