Robert Montal1, Daniela Sia2, Carla Montironi3, Wei Q Leow4, Roger Esteban-Fabró3, Roser Pinyol3, Miguel Torres-Martin2, Laia Bassaganyas3, Agrin Moeini3, Judit Peix3, Laia Cabellos3, Miho Maeda2, Carlos Villacorta-Martin2, Parissa Tabrizian2, Leonardo Rodriguez-Carunchio5, Giancarlo Castellano6, Christine Sempoux7, Beatriz Minguez8, Timothy M Pawlik9, Ismail Labgaa10, Lewis R Roberts11, Manel Sole5, Maria I Fiel2, Swan Thung2, Josep Fuster12, Sasan Roayaie13, Augusto Villanueva14, Myron Schwartz2, Josep M Llovet15. 1. Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, Hospital Clínic, University of Barcelona, Barcelona, Catalonia, Spain; Gastrointestinal Unit, Medical Oncology Department, ICMHO, Hospital Clínic, Barcelona, Catalonia, Spain. 2. Liver Cancer Program, Divisions of Liver Diseases, Pathology Department and RM Transplant Institute, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA. 3. Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, Hospital Clínic, University of Barcelona, Barcelona, Catalonia, Spain. 4. Liver Cancer Program, Divisions of Liver Diseases, Pathology Department and RM Transplant Institute, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Department of Anatomical Pathology, Singapore General Hospital, Duke-NUS Medical School, Singapore. 5. Pathology Department, IDIBAPS-Hospital Clinic Barcelona, University of Barcelona, Catalonia, Spain. 6. Molecular Biology Core, Hospital Clinic, Barcelona, Catalonia, Spain. 7. Service of Clinical Pathology, Institute of Pathology, Lausanne University Hospital CHUV, Lausanne, Switzerland. 8. Liver Unit, Department of Internal Medicine, Vall d'Hebron University Hospital, Vall d'Hebron Institut of Research, Center for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Autonomous University of Barcelona, Barcelona, Spain. 9. Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA. 10. Department of Visceral Surgery, Lausanne University Hospital CHUV, Lausanne, Switzerland. 11. Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA. 12. Hepatobiliary and Pancreatic Surgery Department, IDIBAPS-Hospital Clinic Barcelona, University of Barcelona, Catalonia, Spain. 13. Department of Surgery, White Plains Hospital, White Plains, New York, USA; Division of Hepatobiliary Surgery, Lenox Hill Hospital, New York, New York, USA. 14. Liver Cancer Program, Divisions of Liver Diseases, Pathology Department and RM Transplant Institute, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA. 15. Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, Hospital Clínic, University of Barcelona, Barcelona, Catalonia, Spain; Liver Cancer Program, Divisions of Liver Diseases, Pathology Department and RM Transplant Institute, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain. Electronic address: jmllovet@clinic.cat.
Abstract
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.
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.
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