Genetic and Expression Analysis of MET, MACC1, and HGF in Metastatic Colorectal Cancer: Response to Met Inhibition in Patient Xenografts and Pathologic Correlations
Genetic and Expression Analysis of MET, MACC1, and HGF in Metastatic Colorectal Cancer: Response to Met Inhibition in Patient Xenografts and Pathologic Correlations
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DOI：
10.1158/1078-0432.ccr-10-3377
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发表时间：
2011-05-15
影响因子：
11.5
通讯作者：
Bertotti, Andrea
中科院分区：
文献类型：
--
作者：
Galimi, Francesco;Torti, Davide;Bertotti, Andrea
目的：我们测定了大肠癌肝转移灶（mCRC）中MET、其转录激活因子MACC 1及其配体肝细胞生长因子（HGF）的基因拷贝数。我们将拷贝数与mRNA水平相关联，并探讨MET和MACC 1的获得和/或过表达是否预测对抗Met治疗的反应。最后，我们评估了它们的基因组或转录失调是否与侵袭性疾病的病理和分子参数相关。通过定量PCR（qPCR）测定拷贝数和mRNA。在NOD（非肥胖糖尿病）/SCID（重度联合免疫缺陷）小鼠中植入并扩增了39份样本，以生成接受Met抑制剂JNJ-38877605处理的队列。MACC 1靶点的计算机分析依赖于启动子区域的全基因组定位和来自两个CRC dataset.Results的表达数据：没有检测到MET，MACC 1或HGF的局灶性高级别扩增。分别在21%和8%的病例中观察到7号染色体多体性和p臂增加，并且与Met和MACC 1的较高表达显著相关。患者来源的异种移植物中的Met抑制没有改变肿瘤生长。拷贝数增加和MACC 1过表达与不良病理特征的相关性优于Met过表达。推定的MACC 1目标的生物信息学分析确定元素除了Met，其过度表达cosegregated与侵略性形式的结直肠cancer.Conclusions：在患者来源的异种移植物的实验表明，mCRC不依赖于Met基因组增益和/或过度表达的增长。基于病理相关性和生物信息学分析，MACC 1可能通过Met转录上调以外的机制或除此之外的机制促进CRC进展。临床癌症研究; 17（10）; 3146-56。(C)2011年AACR。
Purpose: We determined the gene copy numbers for MET, for its transcriptional activator MACC1 and for its ligand hepatocyte growth factor (HGF) in liver metastases from colorectal carcinoma (mCRC). We correlated copy numbers with mRNA levels and explored whether gain and/or overexpression of MET and MACC1 predict response to anti-Met therapies. Finally, we assessed whether their genomic or transcriptional deregulation correlates with pathologic and molecular parameters of aggressive disease.Experimental Design: One hundred three mCRCs were analyzed. Copy numbers and mRNA were determined by quantitative PCR (qPCR). Thirty nine samples were implanted and expanded in NOD (nonobese diabetic)/SCID (severe combined immunodeficient) mice to generate cohorts that were treated with the Met inhibitor JNJ-38877605. In silico analysis of MACC1 targets relied on genome-wide mapping of promoter regions and on expression data from two CRC datasets.Results: No focal, high-grade amplifications of MET, MACC1, or HGF were detected. Chromosome 7 polysomy and gain of the p-arm were observed in 21% and 8% of cases, respectively, and significantly correlated with higher expression of both Met and MACC1. Met inhibition in patient-derived xenografts did not modify tumor growth. Copy number gain and overexpression of MACC1 correlated with unfavorable pathologic features better than overexpression of Met. Bioinformatic analysis of putative MACC1 targets identified elements besides Met, whose overexpression cosegregated with aggressive forms of colorectal cancer.Conclusions: Experiments in patient-derived xenografts suggest that mCRCs do not rely on Met genomic gain and/or overexpression for growth. On the basis of pathologic correlations and bioinformatic analysis, MACC1 could contribute to CRC progression through mechanisms other than or additional to Met transcriptional upregulation. Clin Cancer Res; 17(10); 3146-56. (C) 2011 AACR.