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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • 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

Published Date

  • October 2017

Published In

Volume / Issue

  • 7 / 10

Start / End Page

  • 1116 - 1135

PubMed ID

  • 28667006

Pubmed Central ID

  • PMC5628134

Electronic International Standard Serial Number (EISSN)

  • 2159-8290

Digital Object Identifier (DOI)

  • 10.1158/2159-8290.CD-17-0368


  • eng

Conference Location

  • United States