Mixed hepatocellular cholangiocarcinoma tumors: Cholangiolocellular carcinoma is a distinct molecular entity
Mixed hepatocellular cholangiocarcinoma tumors: Cholangiolocellular carcinoma is a distinct molecular entity
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DOI：
10.1016/j.jhep.2017.01.010
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发表时间：
2017-05-01
影响因子：
25.7
通讯作者：
Llovet, Josep M.
中科院分区：
文献类型：
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作者：
Moeini, Agrin;Sia, Daniela;Llovet, Josep M.
背景与目的：混合型肝细胞胆管细胞癌是一种少见且知之甚少的原发性肝癌。方法：对18例经福尔马林固定的混合性肝癌-CCA患者进行了基因表达谱、DNA拷贝数检测和外显子组测序，涵盖了该病的整个组织学谱。使用肝细胞癌(n=164)和肝内胆管细胞癌(n=149)的独立数据集进行比较基因组分析。结果：肝细胞癌-肝内胆管细胞癌的综合基因组分析显示，与干细胞和经典类型相比，胆管细胞癌是一个独特的胆源性实体。CLC肿瘤为神经细胞黏附分子阳性(6/6比1/12，p<；0.001)，染色体稳定(平均染色体畸变率为5.7vs.14.1，p=0.008)，转化生长因子-β信号显著上调，炎症相关和免疫应答信号丰富(p<；0.001)。干细胞肿瘤的特征是spalt样转录因子4(6/8vs.0/10，p<；0.001)，祖细胞样信号丰富，特定的致癌途径(即MYC和胰岛素样生长因子)激活，以及与不良临床结果相关的迹象。在经典型中，iCCA组分的拷贝数变异与肝细胞癌的拷贝数变异显著相关，提示为克隆起源。外显子组测序显示每个肿瘤平均有63个非同义突变(每个肿瘤平均2个驱动突变)。结论：混合型肝癌-CCA是一种异质性肿瘤，干细胞类型预后较差，是肝细胞癌和iCCA成分共同谱系的经典类型。CLC是一种独特的胆源性实体，与染色体稳定性和活跃的转化生长因子-b信号有关。研究综述：混合性肝细胞胆管细胞癌(HCC-CCA)的分子分析表明，胆管细胞癌(CLC)是一种独特的胆源性肿瘤。它没有肝细胞癌的任何特征。然而，在混合型肝细胞癌-CCA中，干细胞型肿瘤具有侵袭性和较差的预后，而经典类型的肿瘤显示出共同的细胞谱系，包括肝细胞癌和肝内CCA成分。由于提供了新的分子资料，混合型肝癌-CCA的病理分类需要重新定义。(C)2017年欧洲肝脏研究协会。爱思唯尔出版，版权所有。
Background & Aims: Mixed hepatocellular cholangiocarcinoma (HCC-CCA) is a rare and poorly understood type of primary liver cancer. We aimed to perform a comprehensive molecular characterization of this malignancy.Methods: Gene expression profiling, DNA copy number detection, and exome sequencing using formalin-fixed samples from 18 patients with mixed HCC-CCA were performed, encompassing the whole histological spectrum of the disease. Comparative genomic analysis was carried out, using independent datasets of HCC (n = 164) and intrahepatic cholangiocarcinoma (iCCA) (n = 149).Results: Integrative genomic analysis of HCC-CCAs revealed that cholangiolocellular carcinoma (CLC) represents a distinct biliaryderived entity compared with the stem-cell and classical types. CLC tumors were neural cell adhesion molecule (NCAM) positive (6/6 vs. 1/12, p < 0.001), chromosomally stable (mean chromosomal aberrations 5.7 vs. 14.1, p = 0.008), showed significant upregulation of transforming growth factor (TGF)-beta signaling and enrichment of inflammation-related and immune response signatures (p < 0.001). Stem-cell tumors were characterized by spaltlike transcription factor 4 (SALL4) positivity (6/8 vs. 0/10, p < 0.001), enrichment of progenitor-like signatures, activation of specific oncogenic pathways (i.e., MYC and insulin-like growth factor [IGF]), and signatures related to poor clinical outcome. In the classical type, there was a significant correlation in the copy number variation of the iCCA and HCC components, suggesting a clonal origin. Exome sequencing revealed an average of 63 non-synonymous mutations per tumor (2 mean driver mutations per tumor). Among those, TP53 was the most frequently mutated gene (6/21, 29%) in HCC-CCAs.Conclusions: Mixed HCC-CCA represents a heterogeneous group of tumors, with the stem-cell type characterized by features of poor prognosis, and the classical type with common lineage for HCC and iCCA components. CLC stands alone as a distinct biliary-derived entity associated with chromosomal stability and active TGF-b signaling.Lay summary: Molecular analysis of mixed hepatocellular cholangiocarcinoma (HCC-CCA) showed that cholangiolocellular carcinoma (CLC) is distinct and biliary in origin. It has none of the traits of hepatocellular carcinoma (HCC). However, within mixed HCC-CCA, stem-cell type tumors shared an aggressive nature and poor outcome, whereas the classic type showed a common cell lineage for both the HCC and the intrahepatic CCA component. The pathological classification of mixed HCC-CCA should be redefined because of the new molecular data provided. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.