MET amplification as a potential therapeutic target in gastric cancer.
MET amplification as a potential therapeutic target in gastric cancer.
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DOI：
10.18632/oncotarget.718
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发表时间：
2013-01
期刊：
影响因子：
--
通讯作者：
Yamada Y
中科院分区：
文献类型：
--
作者：
Kawakami H;Okamoto I;Arao T;Okamoto W;Matsumoto K;Taniguchi H;Kuwata K;Yamaguchi H;Nishio K;Nakagawa K;Yamada Y
我们的目的是调查胃癌中 MET 扩增的患病率以及这种基因改变作为胃癌治疗靶点的潜力。通过使用基于 PCR 的拷贝数测定进行初步筛选，然后对手术中获得的福尔马林固定、石蜡包埋的胃癌标本进行验证性 FISH 分析来评估 MET 扩增。还检查了 MET 酪氨酸激酶抑制剂 (MET-TKI) 对有或没有 MET 扩增的胃癌细胞的影响。 266例胃癌中MET拷贝数中位数为1.7，范围为0.41至21.3。我们对 MET 拷贝数最高的 15 个病例进行了 FISH 分析。在 MET 拷贝数至少为 4 的 4 个可评估病例中证实了 MET 扩增，而在基因拷贝数 <4 的病例中未检测到 MET 扩增。因此，MET 扩增的发生率为 1.5%（266 例中有 4 例）。在具有 MET 扩增的胃癌细胞系中，MET-TKIs 抑制 MET 会导致细胞凋亡的诱导，并伴有下游 MET 信号传导的减弱，但在没有这种遗传改变的胃癌细胞系中则不会。 MET 扩增可识别出一小部分可能对 MET-TKI 产生反应的胃癌患者，但具有临床重要意义。此外，使用基于 PCR 的拷贝数测定进行筛查是减少需要通过 FISH 分析确认 MET 扩增的患者数量的有效方法。
Our aim was to investigate both the prevalence of MET amplification in gastric cancer as well as the potential of this genetic alteration to serve as a therapeutic target in gastric cancer. MET amplification was assessed by initial screening with a PCR-based copy number assay followed by confirmatory FISH analysis in formalin-fixed, paraffin-embedded specimens of gastric cancer obtained at surgery. The effects of MET tyrosine kinase inhibitors (MET-TKIs) in gastric cancer cells with or without MET amplification were also examined. The median MET copy number in 266 cases of gastric cancer was 1.7, with a range of 0.41 to 21.3. We performed FISH analysis for the 15 cases with the highest MET copy numbers. MET amplification was confirmed in the four assessable cases with a MET copy number of at least 4, whereas MET amplification was not detected in those with a gene copy number of <4. The prevalence of MET amplification was thus 1.5% (4 out of 266 cases). Inhibition of MET by MET-TKIs resulted in the induction of apoptosis accompanied by attenuation of downstream MET signaling in gastric cancer cell lines with MET amplification but not in those without this genetic change. MET amplification identifies a small but clinically important subgroup of gastric cancer patients who are likely to respond to MET-TKIs. Furthermore, screening with a PCR-based copy number assay is an efficient way to reduce the number of patients requiring confirmation of MET amplification by FISH analysis.
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DOI：
10.1073/pnas.0508776103
发表时间：
2006-02-14
影响因子：
11.1
作者：
Smolen, GA;Sordella, R;Haber, DA
通讯作者：
Haber, DA
影响因子：
45.3
作者：
Ohtsu, Atsushi;Shah, Manish A.;Kang, Yoon-Koo
通讯作者：
Kang, Yoon-Koo
影响因子：
--
作者：
SERUCA, R;SUIJKERBUIJK, RF;SOBRINHOSIMOES, M
通讯作者：
SOBRINHOSIMOES, M
影响因子：
4.2
作者：
Lee, Jeeyun;Seo, Jin Won;Park, Joon Oh
通讯作者：
Park, Joon Oh
影响因子：
5.7
作者：
Okamoto, Wataru;Okamoto, Isamu;Nakagawa, Kazuhiko
通讯作者：
Nakagawa, Kazuhiko