【原】Nat Commun：全基因组突变筛查揭示肝炎对胆管表型肝癌的影响及其分子多样性

背景和目的

肝癌有诸多分类，其中肝内胆管癌和肝细胞合并胆管癌由于在组织学上显示有不同程度的胆管上皮细胞分化，被定义为有胆管表型的肝癌（LCB），不论有无慢性肝炎的情况下LCB是位列第二位易发生的肝癌，且较肝细胞癌更具有侵袭性且预后差。

方法

为了了解LCB分子水平的改变，研究人员对30个LCB肿瘤样品进行全基因组测序，同时还测序了另外60个常见肝细胞肿瘤样品，分析结果显示，在有肝炎感染的患者中，肝细胞癌和LCB基因突变模式相同，但在未感染肝炎的患者中基因突变模式却不相同。（这表明不同组织学类型的肝癌可能是从肝炎感染患者相同类型细胞衍生而来，比如肝祖细胞）。

结果

通过后续验证性研究，研究人员识别了恶性LCB相关的几种重要的基因的突变，包括TERT启动子，染色质调节因子 ( BAP1，PBRM1 和ARID2 ), 突触结构基因 ( PCLO )，IDH基因和KRAS基因。KRAS和IDHs突变--通常与恶性肿瘤相关，被发现主要存在于未曾患慢性肝炎的癌症患者中。

结论

这项研究揭示了慢性肝炎对肝肿瘤突变的强烈冲击和LCBs的遗传多样性。

Abstract

Intrahepatic cholangiocarcinoma and combined hepatocellular cholangiocarcinoma show varying degrees of biliary epithelial differentiation, which can be defined as liver cancer displaying biliary phenotype (LCB). LCB is second in the incidence for liver cancers with and without chronic hepatitis background and more aggressive than hepatocellular carcinoma (HCC). To gain insight into its molecular alterations, we performed whole-genome sequencing analysis on 30 LCBs. Here we show, the genome-wide substitution patterns of LCBs developed in chronic hepatitis livers overlapped with those of 60 HCCs, whereas those of hepatitis-negative LCBs diverged. The subsequent validation study on 68 LCBs identified recurrent mutations in TERT promoter, chromatin regulators (BAP1, PBRM1 and ARID2), a synapse organization gene (PCLO), IDH genes and KRAS. The frequencies of KRAS and IDHs mutations, which are associated with poor disease-free survival, were significantly higher in hepatitis-negative LCBs. This study reveals the strong impact of chronic hepatitis on the mutational landscape in liver cancer and the genetic diversity among LCBs.