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

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

Cancer Discovery

10.1158/2159-8290.CD-17-0368

http://dx.doi.org/10.1158/2159-8290.cd-17-0368

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

oncology

01 July 2017

Jusakul, A., Cutcutache, I., Yong, C. H., Lim, J. Q., Huang, M. N., Padmanabhan, N., … Ng, L. M. (2017). Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma. Cancer Discovery, 7(10), 1116–1135. 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 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.

Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)

We thank Sir Lambert Cornelias Bronsveld and Lady Bronsveld-Ngo Kim Lian for philanthropic support (B.T. Teh). This work was supported by the Singapore National Medical Research Council [NMRC/STaR/0006/2009 (B.T. Teh), NMRC/STaR/0024/2014 (B.T. Teh), NMRC/CG/012/2013 (B.T. Teh), NMRC/CIRG/1422/2015 (S.G. Rozen), and NMRC/STaR/0026/2015 (P. Tan)], Genome Institute of Singapore (P. Tan), Duke-NUS Medical School (P. Tan, S.G. Rozen), National University of Singapore, the National Research Foundation Singapore, Singapore Ministry of Education under the Research Centres of Excellence initiative (P. Tan), National University Cancer Institute, Singapore (NCIS) Centre Grant NR 13NMR 111OM (P. Tan), the Japan Agency for Medical Research and Development (Practical Research for Innovative Cancer Control, 15ck0106094h0002; T. Shibata), National Cancer Center Research and Development Funds (26-A-5; T. Shibata), Italian Cancer Genome Project (FIRB RBAP10AHJB; A. Scarpa), Associazione Italiana Ricerca sul Cancro (n. 12182; A. Scarpa), Italian Ministry of University Health (FIMP CUP_J33G13000210001; A. Scarpa), the NCI of the NIH (P01CA142538; R. Gordan), and the National Natural Science Foundation of China (NSFC81372825; J. Lai). This study was performed as part of the International Cancer Genome Consortium (ICGC). We thank the Duke-NUS Genome Biology Facility for methylation and gene expression assays, the Genome Institute of Singapore Population Genetics facility for SNP arrays, and the Cytogenetics Laboratory, Department of Molecular Pathology, Singapore General Hospital for FISH analysis. We thank D. Jefferson (New England Medical Center, Tufts University) for H69 cells. We also thank the SingHealth Tissue Repository, Dr. Catherine Guettier, and Dr. Jean-Charles Duclos-Vallée (DHU Hepatinov, Hôpital Paul Brousse, AP-HP, Villejuif, France) for tissue samples.This work was supported by the Singapore National Medical Research Council (NMRC/STaR/0006/2009, NMRC/STaR/0024/2014, NMRC/CG/012/2013, NMRC/CIRG/1422/2015, and NMRC/STaR/0026/2015), Genome Institute of Singapore, Duke-NUS Medical School, National University of Singapore, the National Research Foundation Singapore, Singapore Ministry of Education under the Research Centres of Excellence initiative, Japan Agency for Medical Research and Development (Practical Research for Innovative Cancer Control, 15ck0106094h0002), National Cancer Center Research and Development Funds (26-A-5), Italian Cancer Genome Project (FIRB RBAP10AHJB), Associazione Italiana Ricerca sul Cancro (n. 12182), Italian Ministry of University Health (FIMP CUP_J33G13000210001) and National Natural Science Foundation of China (NSFC81372825). We thank Sir Lambert Cornelias Bronsveld and Lady Bronsveld-Ngo Kim Lian for philanthropic support.

https://oar.a-star.edu.sg/communities-collections/articles/17422

2159-8290
2159-8274

Institute of Molecular and Cell Biology

http://dx.doi.org/10.1158/2159-8290.cd-17-0368