Analysis of Genomes and Transcriptomes of Hepatocellular Carcinomas Identifies Mutations and Gene Expression Changes in the Transforming Growth Factor-β Pathway.
Analysis of Genomes and Transcriptomes of Hepatocellular Carcinomas Identifies Mutations and Gene Expression Changes in the Transforming Growth Factor-β Pathway.
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分析肝细胞癌的基因组和转录组鉴定了转化生长因子-β途径中的突变和基因表达变化。
DOI：
10.1053/j.gastro.2017.09.007
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发表时间：
2018-01
期刊：
影响因子：
29.4
通讯作者：
Mishra L
中科院分区：
文献类型：
--
作者：
Chen J;Zaidi S;Rao S;Chen JS;Phan L;Farci P;Su X;Shetty K;White J;Zamboni F;Wu X;Rashid A;Pattabiraman N;Mazumder R;Horvath A;Wu RC;Li S;Xiao C;Deng CX;Wheeler DA;Mishra B;Akbani R;Mishra L
肝细胞癌（HCC）的发生与转化生长因子β（TGFβ）信号通路的改变有关，该通路调节肝脏炎症并具有肿瘤抑制或促进活性。关于该通路的特定成员在HCC发展中的作用知之甚少。我们采取了一种综合的方法来识别和验证HCC中该途径的变化的影响，并确定治疗靶点。我们对总共488例HCC进行了转录组分析，其中包括来自癌症基因组图谱的数据。我们还筛选了癌症体细胞突变目录中报道的301例HCC和癌症基因组图谱中报道的202例HCC的基因组序列突变。我们在HepG 2、SNU 398和SNU 475细胞中表达了血影蛋白β非红细胞1（SPTBN 1）的突变形式，并测量了SMAD家族成员3（SMAD 3）的磷酸化、核转位和转录活性。我们在38%的HCC样本中发现了至少1个基因的体细胞突变，其产物是TGFβ信号通路的成员。SPTBN 1在最大比例的样本中发生突变（12/202，6%）。转录组数据的无监督聚类鉴定了一组具有TGFβ信号传导途径激活（该途径中基因转录增加）的HCC和一组具有TGFβ信号传导失活（该途径中基因表达减少）的HCC。TGFβ信号转导失活的肿瘤患者的生存时间短于TGFβ信号转导激活的肿瘤患者（P= 0.0129）。TGFβ信号传导模式与DNA损伤反应和sirtuin信号传导途径的激活相关。与表达正常SPTBN 1的细胞（对照）相比，表达D1089 Y突变体或敲低SPTBN 1的HepG 2、SNU 398、SNU 475细胞对DNA交联剂的敏感性增加，存活率降低。在HCC样本的基因组和转录组分析中，我们发现近40%的样本中TGFβ信号通路中的基因突变。这些与通路中基因表达的变化相关;该通路中基因的上调将导致炎症和纤维化，而下调将表明TGFβ肿瘤抑制活性的丧失。我们的研究结果表明，基于TGFβ通路的遗传特征，HCC的治疗药物可能是有效的;阻断TGFβ的药物应仅用于特定类型的HCC患者。
Development of hepatocellular carcinoma (HCC) is associated with alterations in the transforming growth factor beta (TGFβ) signaling pathway, which regulates liver inflammation and can have tumor suppressor or promoter activities. Little is known about the roles of specific members of this pathway at specific of HCC development. We took an integrated approach to identify and validate the effects of changes in this pathway in HCC and identify therapeutic targets. We performed transcriptome analyses for a total of 488 HCCs that include data from The Cancer Genome Atlas. We also screened 301 HCCs reported in the Catalogue of Somatic Mutations in Cancer and 202 from Cancer Genome Atlas for mutations in genome sequences. We expressed mutant forms of spectrin beta, non-erythrocytic 1 (SPTBN1) in HepG2, SNU398, and SNU475 cells and measured phosphorylation, nuclear translocation, and transcriptional activity of SMAD family member 3 (SMAD3). We found somatic mutations in at least 1 gene whose product is a member of TGFβ signaling pathway in 38% of HCC samples. SPTBN1 was mutated in the largest proportion of samples (12/202, 6%). Unsupervised clustering of transcriptome data identified a group of HCCs with activation of the TGFβ signaling pathway (increased transcription of genes in the pathway) and a group of HCCs with inactivation of TGFβ signaling (reduced expression of genes in this pathway). Patients with tumors with inactivation of TGFβ signaling had shorter survival times than patients with tumors with activation of TGFβ signaling (P=.0129). Patterns of TGFβ signaling correlated with activation of the DNA damage response and sirtuin signaling pathways. HepG2, SNU398, SNU475 cells that expressed the D1089Y mutant or with knockdown of SPTBN1 had increased sensitivity to DNA crosslinking agents and reduced survival compared to cells that expressed normal SPTBN1 (controls). In genome and transcriptome analyses of HCC samples, we found mutations in genes in the TGFβ signaling pathway in almost 40% of samples. These correlated with changes in expression of genes in the pathways; upregulation of genes in this pathway would contribute to inflammation and fibrosis whereas downregulation would indicate loss of TGFβ tumor suppressor activity. Our findings indicate that therapeutic agents for HCCs can be effective, based on genetic features of the TGFβ pathway; agents that block TGFβ should be used only in patients with specific types of HCCs.
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影响因子：
64.5
作者：
Cancer Genome Atlas Research Network. Electronic address: wheeler@bcm.edu;Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
3.7
作者：
Meier D;Schindler D
通讯作者：
Schindler D
DOI：
10.1073/pnas.96.26.14949
发表时间：
1999-12-21
影响因子：
11.1
作者：
Glick, A;Popescu, N;Yuspa, SH
通讯作者：
Yuspa, SH
影响因子：
10.5
作者：
Jaramillo MC;Zhang DD
通讯作者：
Zhang DD
影响因子：
15.9
作者：
Chen, Jian;Yao, Zhi-Xing;Mishra, Lopa
通讯作者：
Mishra, Lopa