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

Cholangiocarcinoma (CCA) is a hepatobiliary malignancy exhibiting high incidence in countries with endemic liver-fluke infection. We analysed 489 CCAs from 10 countries, combining whole-genome (71 cases), targeted/exome, copy-number, gene expression, and DNA methylation information. Integrative clustering defined four 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’UTR deletion as a mechanism of FGFR2 upregulation. Integration of non-coding 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. Lastly, our results exemplify how genetics, epigenetics and environmental carcinogens can interplay across different geographies to generate distinct molecular subtypes of cancer.
Authors:
 [1] ;  [2] ;  [3] ;  [4] ;  [2] ;  [5] ;  [6] ;  [7] ;  [8] ;  [9] ;  [10] ;  [11] ;  [12] ;  [11] ;  [13] ;  [11] ;  [3] ;  [3] ;  [14] ;  [11] more »;  [15] ;  [16] ;  [16] ;  [11] ;  [11] ;  [2] ;  [17] ;  [18] ;  [19] ;  [12] ;  [20] ;  [20] ;  [20] ;  [21] ;  [22] ;  [23] ;  [23] ;  [24] ;  [25] ;  [26] ;  [25] ;  [27] ;  [28] ;  [29] ;  [30] ;  [31] ;  [32] ;  [33] ;  [34] ;  [35] ;  [35] ;  [36] ;  [37] ;  [38] ;  [39] ;  [40] ;  [41] ;  [42] « less
  1. Duke-NUS Medical School (Singapore). Program in Cancer and Stem Cell Biology; National Cancer Centre Singapore (Singapore). Lab. of Cancer Epigenome, Division of Medical Science; Khon Kaen Univ. (Thailand). Centre for Research and Development of Medical Diagnostic Lab. and Dept. of Clinical Immunology and Transfusion Sciences
  2. Duke-NUS Medical School (Singapore). Centre for Computational Biology
  3. Duke-NUS Medical School (Singapore). Program in Cancer and Stem Cell Biology; Duke-NUS Medical School (Singapore). Centre for Computational Biology
  4. National Cancer Centre Singapore (Singapore). Lab. of Cancer Epigenome, Division of Medical Science; National Cancer Centre Singapore (Singapore). Lymphoma Genomic Translational Research Lab., Division of Medical Oncology
  5. Duke-NUS Medical School (Singapore). Program in Cancer and Stem Cell Biology
  6. Duke Univ., Durham, NC (United States). Dept. of Biostatistics and Bioinformatics, Center for Genomic and Computational Biology
  7. National Cancer Centre Singapore (Singapore). Lab. of Cancer Epigenome, Division of Medical Science; Khon Kaen Univ. (Thailand). Cholangiocarcinoma Screening and Care Program and Liver Fluke and Cholangiocarcinoma Research Centre; Khon Kaen Univ. (Thailand). Dept. of Pharmacology
  8. National Univ. of Singapore (Singapore). NUS Graduate School for Integrative Sciences and Engineering
  9. National Univ. of Singapore (Singapore). Cancer Science Inst. of Singapore
  10. National Cancer Centre Singapore (Singapore). Division of Medical Oncology
  11. National Cancer Centre Singapore (Singapore). Lab. of Cancer Epigenome, Division of Medical Science
  12. Khon Kaen Univ. (Thailand). Dept. of Biochemistry
  13. Duke-NUS Medical School (Singapore). Program in Cancer and Stem Cell Biology; National Cancer Centre Singapore (Singapore). Lab. of Cancer Epigenome, Division of Medical Science
  14. National Cancer Centre Singapore (Singapore). Lymphoma Genomic Translational Research Lab., Division of Medical Oncology
  15. National Cancer Centre Singapore (Singapore). Lab. of Cancer Epigenome, Division of Medical Science; National Cancer Centre Singapore (Singapore). Division of Radiation Oncology
  16. Singapore General Hospital (Singapore). Cytogenetics Lab., Dept. of Molecular Pathology
  17. Khon Kaen Univ. (Thailand). Cholangiocarcinoma Screening and Care Program and Liver Fluke and Cholangiocarcinoma Research Centre; Khon Kaen Univ. (Thailand). Dept. of Surgery
  18. Khon Kaen Univ. (Thailand). Dept. of Surgery
  19. Khon Kaen Univ. (Thailand). Cholangiocarcinoma Screening and Care Program and Liver Fluke and Cholangiocarcinoma Research Centre
  20. National Cancer Center Research Inst., Tokyo (Japan). Division of Cancer Genomics
  21. Univ. of Tokyo (Japan). Lab. of Molecular Medicine, Human Genome Center, Inst. of Medical Science
  22. Duke-NUS Medical School (Singapore). National Cancer Center Singapore and Office of Clinical Sciences, Division of Surgical Oncology
  23. Singapore General Hospital (Singapore). Dept. of Hepatopancreatobiliary/Transplant Surgery
  24. Singapore General Hospital (Singapore). Dept. of Anatomical Pathology
  25. Fundeni Clinical Inst., Bucharest (Romania). Center of Digestive Diseases and Liver Transplantation
  26. Massachusetts General Hospital and Harvard Medical School, Boston, MA (United States). Edwin L. Steele Lab. for Tumor Biology, Dept. of Radiation Oncology
  27. Hopital Paul Brousse, Villejuif (France)
  28. Chang Gung Memorial Hospital and Chang Gung Univ., Taoyuan (Taiwan). Dept. of Gastroenterology and Hepatology
  29. Chang Gung Memorial Hospital and Chang Gung Univ., Taoyuan (Taiwan). Dept. of of General Surgery
  30. Univ. and Hospital Trust of Verona, Verona (Italy). Applied Research on Cancer Centre (ARC-Net)
  31. First Affiliated Hospital of Sun Yat-sen Univ., Guangzhou (China). Dept. of Hepatobiliary Surgery
  32. Southern Medical Univ., Chenzhou (China). National and Local Joint Engineering Lab. of High-through Molecular Diagnostic Technology
  33. Barretos Cancer Hospital, Barretos, Sao Paulo (Brazil)
  34. Federal Univ. of Sao Paulo, Sao Paulo (Brazil). Lab. of Cancer Molecular Biology, Dept. of Biological Sciences
  35. Yonsei Univ. College of Medicine, Seoul (Korea). Integrated Genomic Research Center for Metabolic Regulation, Dept. of Pathology
  36. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  37. Duke Univ., Durham, NC (United States). Dept. of Biostatistics and Bioinformatics, Center for Genomic and Computational Biology; Duke Univ., Durham, NC (United States). Dept. of Computer Science
  38. Duke-NUS Medical School (Singapore). Program in Cancer and Stem Cell Biology; Duke-NUS Medical School (Singapore). Centre for Computational Biology; National Univ. of Singapore (Singapore). Cancer Science Inst. of Singapore
  39. National Cancer Center Research Inst., Tokyo (Japan). Division of Cancer Genomics; Univ. of Tokyo (Japan). Lab. of Molecular Medicine, Human Genome Center, Inst. of Medical Science
  40. Khon Kaen Univ. (Thailand). Dept. of Pathology, Faculty of Medicine
  41. Duke-NUS Medical School (Singapore). Program in Cancer and Stem Cell Biology; National Cancer Centre Singapore (Singapore). Lab. of Cancer Epigenome, Division of Medical Science; National Univ. of Singapore (Singapore). Cancer Science Inst. of Singapore; SingHealth/Duke-NUS Inst. of Precision Medicine (Singapore). National Heart Centre; Inst. of Molecular and Cell Biology (Singapore)
  42. Duke-NUS Medical School (Singapore). Program in Cancer and Stem Cell Biology; National Univ. of Singapore (Singapore). Cancer Science Inst. of Singapore; National Univ. of Singapore (Singapore). Cancer Science Inst. of Singapore; Genome Inst. of Singapore (Singapore)
Publication Date:
Report Number(s):
LA-UR-16-20750
Journal ID: ISSN 2159-8274
Grant/Contract Number:
AC52-06NA25396
Type:
Accepted Manuscript
Journal Name:
Cancer Discovery
Additional Journal Information:
Journal Volume: 7; Journal Issue: 10; Journal ID: ISSN 2159-8274
Publisher:
American Association for Cancer Research
Research Org:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org:
USDOE Laboratory Directed Research and Development (LDRD) Program; National Institutes of Health (NIH); National Natural Science Foundation of China (NNSFC); Singapore National Medical Research Council
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; Biological Science
OSTI Identifier:
1392801