TY - JOUR
T1 - Molecular classification and therapeutic targets in extrahepatic cholangiocarcinoma
AU - Montal, Robert
AU - Sia, Daniela
AU - Montironi, Carla
AU - Leow, Wei Q.
AU - Esteban-Fabró, Roger
AU - Pinyol, Roser
AU - Torres-Martin, Miguel
AU - Bassaganyas, Laia
AU - Moeini, Agrin
AU - Peix, Judit
AU - Cabellos, Laia
AU - Maeda, Miho
AU - Villacorta-Martin, Carlos
AU - Tabrizian, Parissa
AU - Rodriguez-Carunchio, Leonardo
AU - Castellano, Giancarlo
AU - Sempoux, Christine
AU - Minguez, Beatriz
AU - Pawlik, Timothy M.
AU - Labgaa, Ismail
AU - Roberts, Lewis R.
AU - Sole, Manel
AU - Fiel, Maria I.
AU - Thung, Swan
AU - Fuster, Josep
AU - Roayaie, Sasan
AU - Villanueva, Augusto
AU - Schwartz, Myron
AU - Llovet, Josep M.
N1 - Publisher Copyright:
© 2020 European Association for the Study of the Liver
PY - 2020/8
Y1 - 2020/8
N2 - Background & Aims: 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. Methods: 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. Results: 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. Conclusion: 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. Lay summary: 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.
AB - Background & Aims: 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. Methods: 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. Results: 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. Conclusion: 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. Lay summary: 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.
KW - Biomarkers
KW - Extrahepatic cholangiocarcinoma
KW - Immunotherapy
KW - Liver cancer
KW - Molecular classification
KW - Targeted therapies
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U2 - 10.1016/j.jhep.2020.03.008
DO - 10.1016/j.jhep.2020.03.008
M3 - Article
C2 - 32173382
AN - SCOPUS:85085296443
SN - 0168-8278
VL - 73
SP - 315
EP - 327
JO - Journal of hepatology
JF - Journal of hepatology
IS - 2
ER -