Molecular classification and therapeutic targets in extrahepatic cholangiocarcinoma.

Details

Serval ID
serval:BIB_DF1292E672E3
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Molecular classification and therapeutic targets in extrahepatic cholangiocarcinoma.
Journal
Journal of hepatology
Author(s)
Montal R., Sia D., Montironi C., Leow W.Q., Esteban-Fabró R., Pinyol R., Torres-Martin M., Bassaganyas L., Moeini A., Peix J., Cabellos L., Maeda M., Villacorta-Martin C., Tabrizian P., Rodriguez-Carunchio L., Castellano G., Sempoux C., Minguez B., Pawlik T.M., Labgaa I., Roberts L.R., Sole M., Fiel M.I., Thung S., Fuster J., Roayaie S., Villanueva A., Schwartz M., Llovet J.M.
ISSN
1600-0641 (Electronic)
ISSN-L
0168-8278
Publication state
Published
Issued date
08/2020
Peer-reviewed
Oui
Volume
73
Number
2
Pages
315-327
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
Publication Status: ppublish
Abstract
Cholangiocarcinoma (CCA), a deadly malignancy of the bile ducts, can be classified based on its anatomical location into either intrahepatic (iCCA) or extrahepatic (eCCA), each with different pathogenesis and clinical management. There is limited understanding of the molecular landscape of eCCA and no targeted therapy with clinical efficacy has been approved. We aimed to provide a molecular classification of eCCA and identify potential targets for molecular therapies.
An integrative genomic analysis of an international multicenter cohort of 189 eCCA cases was conducted. Genomic analysis included whole-genome expression, targeted DNA-sequencing and immunohistochemistry. Molecular findings were validated in an external set of 181 biliary tract tumors from the ICGC.
KRAS (36.7%), TP53 (34.7%), ARID1A (14%) and SMAD4 (10.7%) were the most prevalent mutations, with ∼25% of tumors having a putative actionable genomic alteration according to OncoKB. Transcriptome-based unsupervised clustering helped us define 4 molecular classes of eCCA. Tumors classified within the Metabolic class (19%) showed a hepatocyte-like phenotype with activation of the transcription factor HNF4A and enrichment in gene signatures related to bile acid metabolism. The Proliferation class (23%), more common in patients with distal CCA, was characterized by enrichment of MYC targets, ERBB2 mutations/amplifications and activation of mTOR signaling. The Mesenchymal class (47%) was defined by signatures of epithelial-mesenchymal transition, aberrant TGFβ signaling and poor overall survival. Finally, tumors in the Immune class (11%) had a higher lymphocyte infiltration, overexpression of PD-1/PD-L1 and molecular features associated with a better response to immune checkpoint inhibitors.
An integrative molecular characterization identified distinct subclasses of eCCA. Genomic traits of each class provide the rationale for exploring patient stratification and novel therapeutic approaches.
Targeted therapies have not been approved for the treatment of extrahepatic cholangiocarcinoma. We performed a multi-platform molecular characterization of this tumor in a cohort of 189 patients. These analyses revealed 4 novel transcriptome-based molecular classes of extrahepatic cholangiocarcinoma and identified ∼25% of tumors with actionable genomic alterations, which has potential prognostic and therapeutic implications.
Keywords
Aged, B7-H1 Antigen/genetics, Bile Duct Neoplasms/drug therapy, Bile Duct Neoplasms/genetics, Bile Duct Neoplasms/pathology, Cholangiocarcinoma/drug therapy, Cholangiocarcinoma/genetics, Cholangiocarcinoma/pathology, Cohort Studies, Drug Discovery, Europe/epidemiology, Female, Genome-Wide Association Study/methods, Hepatocyte Nuclear Factor 4/genetics, Humans, Immunohistochemistry, Male, Molecular Targeted Therapy/methods, Prognosis, Programmed Cell Death 1 Receptor/genetics, Receptor, ErbB-2/genetics, Sequence Analysis, DNA/methods, Signal Transduction/genetics, United States/epidemiology, Biomarkers, Extrahepatic cholangiocarcinoma, Immunotherapy, Liver cancer, Molecular classification, Targeted therapies
Pubmed
Web of science
Create date
18/03/2020 9:52
Last modification date
14/06/2022 5:36
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