Liver Cancer Cell of Origin, Molecular Class, and Effects on Patient Prognosis
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 prognosi...
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| Published in | Gastroenterology (New York, N.Y. 1943) Vol. 152; no. 4; pp. 745 - 761 |
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| Main Authors | , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Elsevier Inc
01.03.2017
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| Subjects | |
| Online Access | Get full text |
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| 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 30% of HCCs). Further studies of these alterations are needed before they can be used as biomarkers in clinical decision making. |
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| AbstractList | 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. 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 30% of HCCs). Further studies of these alterations are needed before they can be used as biomarkers in clinical decision making. |
| Author | Llovet, Josep M Sia, Daniela Friedman, Scott L Villanueva, Augusto |
| Author_xml | – sequence: 1 fullname: Sia, Daniela – sequence: 2 fullname: Villanueva, Augusto – sequence: 3 fullname: Friedman, Scott L – sequence: 4 fullname: Llovet, Josep M |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/28043904$$D View this record in MEDLINE/PubMed |
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| Keywords | hepatitis B virus mechanistic target of rapamycin intrahepatic cholangiocarcinoma hepatitis C virus interleukin HBV hepatocellular carcinoma mixed hepatocellular cholangiocarcinoma PSC IL next-generation sequencing HCC-CCA iCCA HCC ▪ MTOR TGF cholangiolocellular carcinoma fibrolamellar hepatocellular carcinoma HCV CLC NGS FLC transforming growth factor primary sclerosing cholangitis Prognosis Liver Cancer Molecular Drivers Targeted Therapies |
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| Snippet | 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... |
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| SubjectTerms | Animals Bile Duct Neoplasms - classification Bile Duct Neoplasms - genetics Bile Duct Neoplasms - metabolism Bile Duct Neoplasms - pathology Bile Ducts, Intrahepatic Biomarkers, Tumor Carcinogenesis - pathology Carcinoma, Hepatocellular - classification Carcinoma, Hepatocellular - genetics Carcinoma, Hepatocellular - metabolism Carcinoma, Hepatocellular - pathology Cell Dedifferentiation Cell Proliferation Cell Transdifferentiation Cholangiocarcinoma - classification Cholangiocarcinoma - genetics Cholangiocarcinoma - metabolism Cholangiocarcinoma - pathology Gastroenterology and Hepatology Hepatocytes - pathology Humans Liver Cancer Liver Neoplasms - classification Liver Neoplasms - genetics Liver Neoplasms - metabolism Liver Neoplasms - pathology Molecular Drivers Prognosis Stem Cells - pathology Targeted Therapies Tumor Escape |
| Title | Liver Cancer Cell of Origin, Molecular Class, and Effects on Patient Prognosis |
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