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

• Published in: Cancer discovery 2017-10, Vol.7 (10), p.1116-1135
• Main Authors: Jusakul, Apinya, Cutcutache, Ioana, Yong, Chern Han, Lim, Jing Quan, Huang, Mi Ni, Padmanabhan, Nisha, Nellore, Vishwa, Kongpetch, Sarinya, Ng, Alvin Wei Tian, Ng, Ley Moy, Choo, Su Pin, Myint, Swe Swe, Thanan, Raynoo, Nagarajan, Sanjanaa, Lim, Weng Khong, Ng, Cedric Chuan Young, Boot, Arnoud, Liu, Mo, Ong, Choon Kiat, Rajasegaran, Vikneswari, Lie, Stefanus, Lim, Alvin Soon Tiong, Lim, Tse Hui, Tan, Jing, Loh, Jia Liang, McPherson, John R, Khuntikeo, Narong, Bhudhisawasdi, Vajaraphongsa, Yongvanit, Puangrat, Wongkham, Sopit, Totoki, Yasushi, Nakamura, Hiromi, Arai, Yasuhito, Yamasaki, Satoshi, Chow, Pierce Kah-Hoe, Chung, Alexander Yaw Fui, Ooi, London Lucien Peng Jin, Lim, Kiat Hon, Dima, Simona, Duda, Dan G, Popescu, Irinel, Broet, Philippe, Hsieh, Sen-Yung, Yu, Ming-Chin, Scarpa, Aldo, Lai, Jiaming, Luo, Di-Xian, Carvalho, André Lopes, Vettore, André Luiz, Rhee, Hyungjin, Park, Young Nyun, Alexandrov, Ludmil B, Gordân, Raluca, Rozen, Steven G, Shibata, Tatsuhiro, Pairojkul, Chawalit, Teh, Bin Tean, Tan, Patrick
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; BASIC BIOLOGICAL SCIENCES; Bile Duct Neoplasms - genetics; Biological Science; Cholangiocarcinoma - genetics; CpG Islands; DNA Methylation; Epigenomics - methods; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Genome-Wide Association Study - methods; Humans; Receptor, ErbB-2 - genetics; Receptor, Fibroblast Growth Factor, Type 2 - genetics; Tumor Suppressor Protein p53 - genetics
• ISSN: 2159-8274; 2159-8290
• DOI: 10.1158/2159-8290.cd-17-0368

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 amplifications and mutations; conversely, fluke-negative CCAs (clusters 3/4) exhibit high copy-number alterations and / expression, or epigenetic mutations ( ) and / -related gene rearrangements. Whole-genome analysis highlighted 3' untranslated region deletion as a mechanism of 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. 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. .