Impact of MET amplification on gastric cancer: Possible roles as a novel prognostic marker and a potential therapeutic target
Impact of MET amplification on gastric cancer: Possible roles as a novel prognostic marker and a potential therapeutic target
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DOI：
10.3892/or.2011.1219
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发表时间：
2011-06-01
期刊：
影响因子：
4.2
通讯作者：
Park, Joon Oh
中科院分区：
文献类型：
--
作者：
Lee, Jeeyun;Seo, Jin Won;Park, Joon Oh
识别在控制肿瘤生长和存活中起关键作用的关键基因将为开发治疗靶点奠定基础。鉴于MET扩增的胃癌细胞系对c-Met抑制剂的极端敏感性，为了建立用于治疗实体瘤的个性化药物，我们专注于胃癌患者中的MET扩增。我们检测了来自482名接受根治性手术的胃癌患者的各种胃癌细胞系和组织样本中MET扩增和c-Met活化。通过定量实时PCR（qPCR）和FISH进行MET扩增的胃癌细胞系预测了对PHA-665，752（一种选择性c-Met激酶抑制剂）的敏感性。在472例具有可用于qPCR分析的DNA样本的患者中，100例患者（21.2%）的MET拷贝数大于4.0拷贝，并且在根治性手术后表现出较差的生存率，具有统计学显著性（5年OS; 50.0 vs. 59.1%; MET扩增（+）vs. MET扩增（-）; P=0.0134）。这些结果表明，通过qPCR测量的增加的MET拷贝数在确定胃癌患者的预后中起重要作用。然而，MET扩增对治疗反应的预测作用应在即将进行的临床试验中进一步探索。
Identification of critical genes which play pivotal roles in controlling tumor growth and survival will establish the basis for developing therapeutic targets. With the aim of establishing personalized medicine for treatment of solid tumors, we focused on MET amplification in gastric cancer patients, given the extreme sensitivity to c-Met inhibitor in MET amplified gastric cancer cell lines. We tested MET amplification and activation of c-Met in various gastric cancer cell lines and tissue samples from 482 gastric cancer patients who underwent curative surgery. Gastric cancer cell lines with MET amplification by quantitative real-time PCR (qPCR) and FISH predicted sensitivity to PHA-665,752, a selective c-Met kinase inhibitor. Of the 472 patients who had DNA sample available for qPCR analysis, 100 patients (21.2%) had a MET copy number greater than 4.0 copies and demonstrated poorer survival following curative surgery with statistical significance (5-year OS; 50.0 vs. 59.1%; MET amplification (+) vs. MET amplification (-); P=0.0134). These results suggest that the increased MET copy number measured by qPCR plays an important role in determining prognosis in gastric cancer patients. However, the predictive role of MET amplification for treatment response should be further explored in upcoming clinical trials.