cancer Cell:中国科学家揭示混合型肝癌分子特征和诊断标志物

2019-05-25 CellPress细胞科学 Cell Press

原发性肝癌(简称肝癌)每年造成全球约70万病人死亡且过半死亡病例来自中国,其致死率在所有癌种中高居第二。肝癌主要分为三种类型,肝细胞癌(~80%)、肝内胆管癌(~15%)和混合型肝癌(~5%)。混合型肝癌兼具肝细胞癌和胆管细胞癌两种成分,是预后最差的一种肝癌。目前,混合型肝癌的分子特征未知,缺乏准确诊断标志物,因此其精确诊断和靶向治疗一直是原发性肝癌领域的重大难题。

原发性肝癌(简称肝癌)每年造成全球约70万病人死亡且过半死亡病例来自中国,其致死率在所有癌种中高居第二。肝癌主要分为三种类型,肝细胞癌(~80%)、肝内胆管癌(~15%)和混合型肝癌(~5%)。混合型肝癌兼具肝细胞癌和胆管细胞癌两种成分,是预后最差的一种肝癌。目前,混合型肝癌的分子特征未知,缺乏准确诊断标志物,因此其精确诊断和靶向治疗一直是原发性肝癌领域的重大难题。

Cell Press细胞出版社旗下的Cancer Cell在线发表了北京大学第一医院张宁团队、北京大学生物医学前沿创新中心(BIOPIC)白凡团队、中山大学肿瘤防治中心曾木圣团队和日本理化研究所(RIKEN)中川英刀团队联合主导的国际合作研究成果。在题为“Genomic and Transcriptomic Profiling of Combined Hepatocellular and Intrahepatic Cholangiocarcinoma Reveals Distinct Molecular Subtypes”的论文中,研究人员综合利用多种测序方法、数据分析和实验手段,系统研究了混合型肝癌三种病理亚型的基因组特征,提出了混合型肝癌分子分型标准,揭示了混合型肝癌中肝细胞癌和胆管细胞癌两种成分的克隆起源关系,发现了新的诊断和预后标志物,这些结果为混合型肝癌的临床诊断、预后和治疗提供了关键信息。

此项研究中,研究人员从天津肿瘤医院、中山大学肿瘤防治中心、日本广岛医学中心和新加坡总医院等8家医院收集了133例混合型肝癌病例的临床样本和病例信息进行研究。为了深入探究混合型肝癌中两种病理成分的克隆起源关系,本研究根据两种成分的物理分布,将混合型肝癌分为三个亚型:Separate type (分开型)、Combined type (结合型) 和 Mixed type (混匀型),并且针对三种亚型分别设计了针对性研究方案。

首先,经过外显子测序,全基因组测序和转录组测序,研究人员系统分析了混合型肝癌的高频驱动事件,包括体细胞突变、HBV插入位点、拷贝数变异,融合基因,结构变异,差异表达基因等,全面绘制了混合型肝癌的基因组图谱。随后通过同TCGA,ICGC等国际和国内组织发表的肝细胞癌和胆管细胞癌数据综合比较,研究人员发现,混合型肝癌中显着富集TP53突变,同时缺乏肝细胞癌中富集的CTNNB1突变,缺乏胆管细胞癌中富集的KRAS突变,该结果初步揭示了混合型肝癌独特的基因组特征。

其次,通过分子分型探究,研究人员发现Combined type (结合型)混合型肝癌同胆管细胞癌分子图谱相近,而Mixed type (混匀型)混合型肝癌同肝细胞癌分子图谱相近,而且研究人员发现这两种亚型的免疫微环境也存在较大差异,暗示其对免疫治疗的应答会有所不同。这些结果提示这两种病理类型混合型肝癌应该采取不同的治疗方案。

第三,通过激光显微切割,突变肿瘤细胞占比分析和单细胞测序等技术,研究人员分析和比较了混合型肝癌中的肝细胞癌和胆管细胞癌两种成分,发现这两种成分既有单克隆起源也有多克隆起源。同时,通过重构亚克隆组分析,研究人员还推断了Separate type (分开型)的肿瘤转移路径,揭示了其表型转化和演化规律。

最后,研究人员发现Nestin蛋白表达可以作为混合型肝癌的诊断和预后标志物。 免疫组化分析结果显示,Nestin 蛋白在混合型肝癌中的表达水平和阳性率均显着高于肝细胞癌和胆管细胞癌。通过分析预后数据,Nestin 阳性表达病例在混合型肝癌中呈现显着较差的预后,而且这一发现同样适用于肝细胞癌和肝内胆管癌。这些结果说明,Nestin蛋白可以作为混合型肝癌乃至肝细胞癌和肝内胆管癌的预后标志物。

原始出处:
Ruidong Xue,Lu Chen,Chong Zhang,et al.Genomic and Transcriptomic Profiling of Combined Hepatocellular and Intrahepatic Cholangiocarcinoma Reveals Distinct Molecular Subtypes,cancer cell.Published:May 23,2019DOI:https://doi.org/10.1016/j.ccell.2019.04.007

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    2020-04-17 维他命
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  7. 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    2019-05-25 留走人康

    肝癌,接下来就要细分了,对于体质好的病人,能否将PD-1类+抗血管新生+放疗等相结合,甚至有必要用TACE进行减负

    0

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