Skip to main content

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

Publication ,  Journal Article
Jusakul, A; Cutcutache, I; Yong, CH; Lim, JQ; Huang, MN; Padmanabhan, N; Nellore, V; Kongpetch, S; Ng, AWT; Ng, LM; Choo, SP; Myint, SS ...
Published in: Cancer Discov
October 2017

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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Cancer Discov

DOI

EISSN

2159-8290

Publication Date

October 2017

Volume

7

Issue

10

Start / End Page

1116 / 1135

Location

United States

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Receptor, erbB-2
  • Receptor, Fibroblast Growth Factor, Type 2
  • Receptor, ErbB-2
  • Humans
  • Genome-Wide Association Study
  • Gene Regulatory Networks
  • Gene Expression Regulation, Neoplastic
  • Epigenomics
  • DNA Methylation
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Jusakul, A., Cutcutache, I., Yong, C. H., Lim, J. Q., Huang, M. N., Padmanabhan, N., … Tan, P. (2017). Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma. Cancer Discov, 7(10), 1116–1135. https://doi.org/10.1158/2159-8290.CD-17-0368
Jusakul, Apinya, Ioana Cutcutache, Chern Han Yong, Jing Quan Lim, Mi Ni Huang, Nisha Padmanabhan, Vishwa Nellore, et al. “Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma.Cancer Discov 7, no. 10 (October 2017): 1116–35. https://doi.org/10.1158/2159-8290.CD-17-0368.
Jusakul A, Cutcutache I, Yong CH, Lim JQ, Huang MN, Padmanabhan N, et al. Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma. Cancer Discov. 2017 Oct;7(10):1116–35.
Jusakul, Apinya, et al. “Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma.Cancer Discov, vol. 7, no. 10, Oct. 2017, pp. 1116–35. Pubmed, doi:10.1158/2159-8290.CD-17-0368.
Jusakul A, Cutcutache I, Yong CH, Lim JQ, Huang MN, Padmanabhan N, Nellore V, Kongpetch S, Ng AWT, Ng LM, Choo SP, Myint SS, Thanan R, Nagarajan S, Lim WK, Ng CCY, Boot A, Liu M, Ong CK, Rajasegaran V, Lie S, Lim AST, Lim TH, Tan J, Loh JL, McPherson JR, Khuntikeo N, Bhudhisawasdi V, Yongvanit P, Wongkham S, Totoki Y, Nakamura H, Arai Y, Yamasaki S, Chow PK-H, Chung AYF, Ooi LLPJ, Lim KH, Dima S, Duda DG, Popescu I, Broet P, Hsieh S-Y, Yu M-C, Scarpa A, Lai J, Luo D-X, Carvalho AL, Vettore AL, Rhee H, Park YN, Alexandrov LB, Gordân R, Rozen SG, Shibata T, Pairojkul C, Teh BT, Tan P. Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma. Cancer Discov. 2017 Oct;7(10):1116–1135.

Published In

Cancer Discov

DOI

EISSN

2159-8290

Publication Date

October 2017

Volume

7

Issue

10

Start / End Page

1116 / 1135

Location

United States

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Receptor, erbB-2
  • Receptor, Fibroblast Growth Factor, Type 2
  • Receptor, ErbB-2
  • Humans
  • Genome-Wide Association Study
  • Gene Regulatory Networks
  • Gene Expression Regulation, Neoplastic
  • Epigenomics
  • DNA Methylation