title: Liver Cancer Cell of Origin, Molecular Class, and Effects on Patient Prognosis.
abstract: Primary liver cancer is the second leading cause of cancer-related death worldwide and therefore a major public health challenge. We review hypotheses of the cell of origin of liver tumorigenesis and clarify the classes of liver cancer based on molecular features and how they affect patient prognosis. Primary liver cancer comprises hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), and other rare tumors, notably fibrolamellar carcinoma and hepatoblastoma. The molecular and clinical features of HCC versus iCCA are distinct, but these conditions have overlapping risk factors and pathways of oncogenesis. A better understanding of the cell types originating liver cancer can aid in exploring molecular mechanisms of carcinogenesis and therapeutic options. Molecular studies have identified adult hepatocytes as the cell of origin. These cells have been proposed to transform directly into HCC cells (via a sequence of genetic alterations), to dedifferentiate into hepatocyte precursor cells (which then become HCC cells that express progenitor cell markers), or to transdifferentiate into biliary-like cells (which give rise to iCCA). Alternatively, progenitor cells also give rise to HCCs and iCCAs with markers of progenitor cells. Advances in genome profiling and next-generation sequencing have led to the classification of HCCs based on molecular features and assigned them to categories such as proliferation-progenitor, proliferation-transforming growth factor β, and Wnt-catenin β1. iCCAs have been assigned to categories of proliferation and inflammation. Overall, proliferation subclasses are associated with a more aggressive phenotype and poor outcome of patients, although more specific signatures have refined our prognostic abilities. Analyses of genetic alterations have identified those that might be targeted therapeutically, such as fusions in the FGFR2 gene and mutations in genes encoding isocitrate dehydrogenases (in approximately 60% of iCCAs) or amplifications at 11q13 and 6p21 (in approximately 15% of HCCs). Further studies of these alterations are needed before they can be used as biomarkers in clinical decision making.
authors.affiliation: Mount Sinai Liver Cancer Program, Divisions of Liver Diseases, Hematology, and Medical Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Daniela
authors.initials: D
authors.lastname: Sia
authors.affiliation: Mount Sinai Liver Cancer Program, Divisions of Liver Diseases, Hematology, and Medical Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Augusto
authors.initials: A
authors.lastname: Villanueva
authors.affiliation: Mount Sinai Liver Cancer Program, Divisions of Liver Diseases, Hematology, and Medical Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Friedman
authors.affiliation: Mount Sinai Liver Cancer Program, Divisions of Liver Diseases, Hematology, and Medical Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Liver Cancer Translational Research Laboratory, BCLC, Liver Unit, CIBEREHD, IDIBAPS, Hospital Clinic, University of Barcelona, Barcelona, Catalonia, Spain; Institució Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia, Spain. Electronic address: josep.llovet@mssm.edu.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Llovet
mesh_terms: D000818:Animals; D001650:Bile Duct Neoplasms / Q000145:classification / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D001653:Bile Ducts, Intrahepatic; D014408:Biomarkers, Tumor; D063646:Carcinogenesis / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000145:classification / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D054337:Cell Dedifferentiation; D049109:Cell Proliferation; D054338:Cell Transdifferentiation; D018281:Cholangiocarcinoma / Q000145:classification / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D022781:Hepatocytes / Q000473:pathology*; D006801:Humans; D008113:Liver Neoplasms / Q000145:classification / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D013234:Stem Cells / Q000473:pathology; D019139:Tumor Escape
chemical_list: D014408:Biomarkers, Tumor
keywords: Liver Cancer; Molecular Drivers; Prognosis; Targeted Therapies