Liver Cancer Cell of Origin, Molecular Class, and Effects on Patient Prognosis
Liver Cancer Cell of Origin, Molecular Class, and Effects on Patient Prognosis
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DOI：
10.1053/j.gastro.2016.11.048
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发表时间：
2017-03-01
期刊：
影响因子：
29.4
通讯作者：
Llovet, Josep M.
中科院分区：
文献类型：
--
作者：
Sia, Daniela;Villanueva, Augusto;Llovet, Josep M.
原发性肝癌是全球癌症相关死亡的第二大原因，因此是一项重大的公共卫生挑战。我们回顾了肝脏肿瘤起源细胞的假设，并根据分子特征阐明肝癌的分类及其对患者预后的影响。原发性肝癌包括肝细胞癌（HCC）、肝内胆管癌（iCCA）和其他罕见肿瘤，尤其是纤维板层癌和肝母细胞瘤。HCC与iCCA的分子和临床特征是不同的，但这些情况具有重叠的危险因素和肿瘤发生途径。更好地了解肝癌的细胞类型有助于探索癌变的分子机制和治疗选择。分子研究已经确定成人肝细胞是起源细胞。这些细胞被认为可以直接转化为HCC细胞（通过一系列遗传改变），去分化为肝细胞前体细胞（然后成为表达祖细胞标记的HCC细胞），或者转分化为胆道样细胞（产生iCCA）。或者，祖细胞也产生具有祖细胞标记的hcc和iCCAs。基因组谱分析和下一代测序技术的进步使得基于分子特征对hcc进行分类，并将其划分为增殖祖细胞、增殖转化生长因子β和Wnt-catenin β 1等类别。icca被分为增殖和炎症两类。总体而言，增殖亚类与更具侵袭性的表型和较差的患者预后相关，尽管更具体的特征改进了我们的预后能力。对遗传改变的分析已经确定了那些可能成为治疗目标的基因，例如FGFR2基因的融合和编码异柠檬酸脱氢酶的基因突变（约60%的iCCAs）或11q13和6p21的扩增（约15%的hcc）。在将这些改变用作临床决策的生物标志物之前，需要对它们进行进一步的研究。
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 beta, and Wnt-catenin beta 1. 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.