Genomic Analysis of Vascular Invasion in HCC Reveals Molecular Drivers and Predictive Biomarkers.
Genomic Analysis of Vascular Invasion in HCC Reveals Molecular Drivers and Predictive Biomarkers.
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HCC 血管侵袭的基因组分析揭示了分子驱动因素和预测生物标志物。
DOI：
10.1002/hep.31614
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发表时间：
2021-06
期刊：
影响因子：
--
通讯作者：
Dhanasekaran R
中科院分区：
文献类型：
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作者：
Krishnan MS;Rajan Kd A;Park J;Arjunan V;Garcia Marques FJ;Bermudez A;Girvan OA;Hoang NS;Yin J;Nguyen MH;Kothary N;Pitteri S;Felsher DW;Dhanasekaran R
血管侵犯是肝细胞癌（HCC）复发和生存率低的关键危险因素。HCC中血管侵袭的分子驱动因素在很大程度上是未知的。破译侵袭性HCC的分子景观将有助于确定新的治疗靶点和非侵袭性生物标志物。为此，我们进行了这项研究，以评估基因组，转录组和蛋白质组谱的肿瘤血管浸润使用多平台癌症基因组图谱（TCGA）数据（n=373）。在TCGA肝细胞癌（LIHC）队列中，5%（n=17）的肿瘤存在大血管浸润，25%（n=94）的肿瘤存在微血管浸润。功能通路分析显示，MYC癌基因是血管侵袭中mRNA、miRNA和蛋白质组变化的共同上游调节因子。我们对侵袭性人HCC和MYC驱动的小鼠HCC进行了比较蛋白质组学分析，并确定纤连蛋白是侵袭性HCC的蛋白质组学生物标志物（小鼠Fn 1 p= 1.7 × 10−11;人FN 1 p=1.5 × 10−4），在两个物种中保守。从机制上讲，我们发现FN 1促进了HCC癌细胞的迁移和侵袭表型。我们使用一个大的独立的人类HCC组织微阵列队列证实了人HCC中纤连蛋白的组织过表达（n=153; p<0.001）。最后，我们发现，与肝硬化患者（n=10，平均值=41.8 μg/ml，SEM =13.3; p<0.0001）相比，HCC患者（n=35，平均值=307.7 μg/ml，SEM=35.9）的血浆纤连蛋白水平显著升高。我们的研究评估了具有血管侵袭的肿瘤的分子景观，确定了由MYC癌基因驱动的不同的转录、表观遗传和蛋白质组变化。我们发现MYC上调纤维连接蛋白的表达，从而促进HCC的侵袭性。此外，我们确定纤连蛋白是一个有前途的非侵入性的蛋白质组生物标志物的血管浸润在肝癌。
Vascular invasion is a critical risk factor for hepatocellular carcinoma (HCC) recurrence and poor survival. The molecular drivers of vascular invasion in HCC are largely unknown. Deciphering the molecular landscape of invasive HCC will help identify novel therapeutic targets and noninvasive biomarkers. To this end, we undertook this study to evaluate the genomic, transcriptomic, and proteomic profile of tumors with vascular invasion using the multi-platform cancer genome atlas (TCGA) data (n=373). In the TCGA liver hepatocellular carcinoma (LIHC) cohort, macrovascular invasion was present in 5% (n=17) of tumors and microvascular invasion in 25% (n=94) of tumors. Functional pathway analysis revealed that the MYC oncogene was a common upstream regulator of the mRNA, miRNA and proteomic changes in vascular invasion. We performed comparative proteomic analyses of invasive human HCC and MYC driven murine HCC and identified fibronectin to be proteomic biomarker of invasive HCC (mouse Fn1 p= 1.7 × 10−11; human FN1 p=1.5 × 10−4) conserved across the two species. Mechanistically, we show that FN1 promotes the migratory and invasive phenotype of HCC cancer cells. We demonstrate tissue overexpression of fibronectin in human HCC using a large independent cohort of human HCC tissue microarray (n=153; p<0.001). Lastly, we showed that plasma fibronectin levels were significantly elevated in patients with HCC (n=35, mean=307.7 μg/ml, SEM=35.9) when compared to cirrhosis (n=10, mean=41.8 μg/ml, SEM=13.3; p<0.0001). Our study evaluates the molecular landscape of tumors with vascular invasion, identifying distinct transcriptional, epigenetic and proteomic changes driven by the MYC oncogene. We show that MYC upregulates fibronectin expression which promotes HCC invasiveness. In addition, we identify fibronectin to be a promising non-invasive proteomic biomarker of vascular invasion in HCC.
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影响因子：
--
作者：
Dhanasekaran R;Gabay-Ryan M;Baylot V;Lai I;Mosley A;Huang X;Zabludoff S;Li J;Kaimal V;Karmali P;Felsher DW
通讯作者：
Felsher DW
影响因子：
8.8
作者：
Kurokawa T;Yamazaki S;Mitsuka Y;Moriguchi M;Sugitani M;Takayama T
通讯作者：
Takayama T
实现癌症基因组数据的共同愿景。
DOI：
10.1056/nejmp1607591
发表时间：
2016-09-22
期刊：
The New England journal of medicine
影响因子：
--
作者：
Grossman RL;Heath AP;Ferretti V;Varmus HE;Lowy DR;Kibbe WA;Staudt LM
通讯作者：
Staudt LM
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：
11.2
作者：
Hoshida Y;Nijman SM;Kobayashi M;Chan JA;Brunet JP;Chiang DY;Villanueva A;Newell P;Ikeda K;Hashimoto M;Watanabe G;Gabriel S;Friedman SL;Kumada H;Llovet JM;Golub TR
通讯作者：
Golub TR