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 RajasegaranStefanus 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, Andre Lopes Carvalho, Andre Luiz Vettore, Hyungjin Rhee, Young Nyun Park, Ludmil B. Alexandrov, Raluca Gordan, Steven G. Rozen, Tatsuhiro Shibata, Chawalit Pairojkul, Bin Tean Teh, Patrick Tan*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

687 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1116-1135
Number of pages20
JournalCancer Discovery
Volume7
Issue number10
DOIs
StatePublished - 10 2017
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2017 American Association for Cancer Research.

Fingerprint

Dive into the research topics of 'Whole-genome and epigenomic landscapes of etiologically distinct subtypes of cholangiocarcinoma'. Together they form a unique fingerprint.

Cite this