Accumulation of Molecular Aberrations Distinctive to Hepatocellular Carcinoma Progression
Accumulation of Molecular Aberrations Distinctive to Hepatocellular Carcinoma Progression
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DOI：
10.1158/0008-5472.can-20-0225
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发表时间：
2020-09-15
期刊：
影响因子：
11.2
通讯作者：
Aburatani, Hiroyuki
中科院分区：
文献类型：
--
作者：
Midorikawa, Yutaka;Yamamoto, Shogo;Aburatani, Hiroyuki
癌症通过遗传和表观遗传畸变的积累而发展。为了确定肝细胞癌（HCC）发展过程中发生的连续分子改变，我们通过基因组测序比较了52例早期和108例明显HCC样本。p53/RB 1通路、WNT通路、MLL蛋白家族、SWI/SNF复合物和AKT/PI 3 K通路的基因突变在HCC中是常见的。在所有实体的早期阶段，由于不同的机制，TERT是最频繁上调的基因。尽管驱动基因（包括CTNNB 1和TP 53）中经常发生体细胞突变，但早期HCC是与显性HCC不同的分子实体，因为每种都有不同的表达谱。值得注意的是，无论CTNNB 1突变状态如何，WNT靶基因在早期HCC中都没有被激活，因为由于膜上的E-钙粘蛋白/b-连环蛋白复合物，b-连环蛋白没有易位到细胞核中。相反，WNT靶点在明显的HCC中明确上调，CTNNB 1突变与靶基因中CDH 1的下调和CpG岛的低甲基化相关。类似地，p53/RB通路下游的细胞周期基因仅在显性HCC中上调，TP 53或RB 1基因突变与染色体4 q或16 q缺失相关。HCC在表观遗传学上分为四个亚类：正常样甲基化、整体低甲基化（预后良好）、干样甲基化（预后不良）和CpG岛甲基化。这些甲基化状态在HCC进展过程中总体上得以维持。总的来说，这些数据表明，随着肝癌的进展，额外的分子事件排除驱动基因突变合作有助于转录激活的下游目标根据methylation status.Significance：除了驱动基因突变的WNT和p53途径，进一步的分子事件需要异常转录激活这些途径作为肝癌的进展。
Cancer develops through the accumulation of genetic and epigenetic aberrations. To identify sequential molecular alterations that occur during the development of hepatocellular carcinoma (HCC), we compared 52 early and 108 overt HCC samples by genome sequencing. Gene mutations in the p53/RB1 pathway, WNT pathway, MLL protein family, SWI/SNF complexes, and AKT/PI3K pathway were common in HCC. In the early phase of all entities, TERT was the most frequently upregulated gene owing to diverse mechanisms. Despite frequent somatic mutations in driver genes, including CTNNB1 and TP53, early HCC was a separate molecular entity from overt HCC, as each had a distinct expression profile. Notably, WNT target genes were not activated in early HCC regardless of CTNNB1 mutation status because b-catenin did not translocate into the nucleus due to the E-cadherin/b-catenin complex at the membrane. Conversely, WNT targets were definitively upregulated in overt HCC, with CTNNB1 mutation associated with downregulation of CDH1 and hypomethylation of CpG islands in target genes. Similarly, cell-cycle genes downstream of the p53/RB pathway were upregulated only in overt HCC, with TP53 or RB1 gene mutations associated with chromosomal deletion of 4q or 16q. HCC was epigenetically distinguished into four subclasses: normal-like methylation, global-hypomethylation (favorable prognosis), stem-like methylation (poor prognosis), and CpG island methylation. These methylation statuses were globally maintained through HCC progression. Collectively, these data show that as HCC progresses, additional molecular events exclusive of driver gene mutations cooperatively contribute to transcriptional activation of downstream targets according to methylation status.Significance: In addition to driver gene mutations in the WNT and p53 pathways, further molecular events are required for aberrant transcriptional activation of these pathways as HCC progresses.