Onozato Ryoichi, Kosaka Takayuki, Kuwano Hiroyuki, Sekido Yoshitaka, Yatabe Yasushi, Mitsudomi Tetsuya
Department of Thoracic Surgery, Aichi Cancer Center Hospital, Nagoya, Japan.
J Thorac Oncol. 2009 Jan;4(1):5-11. doi: 10.1097/JTO.0b013e3181913e0e.
MET (Met proto-oncogene) activation either by gene amplification or mutation is implicated in various types of human cancers. For lung cancer, MET gene amplification is reported to occur in a subset of adenocarcinomas. Although somatic mutations of MET in lung adenocarcinomas are rare, all but one of those reported so far entail a splice mutation deleting the juxtamembrane domain for binding the c-Cbl E3-ligase; normally such binding leads to ubiquitination and receptor degradation, and loss of this domain leads to MET activation. The purpose of this study was to clarify in the role of MET activation in lung carcinogenesis.
MET gene copy number was determined by real-time quantitative polymerase chain reaction in 187 of the patients with lung cancer and the MET gene splice mutation deleting the juxtamembrane domain was examined by direct sequencing in 262. The results were correlated with various clinical and pathologic features including mutations of the epidermal growth factor receptor, KRAS, and HER2 genes.
All the instances of MET activation occurred in patients with adenocarcinomas. The prevalences of MET gene amplification and splice mutations were 1.4% (2 of 148) and 3.3% (7 of 211), respectively. We identified four different intronic mutations that disrupted a splice consensus sequence in genomic DNA. Activation of MET and mutations of the epidermal growth factor receptor, KRAS, and HER2 genes had strict mutual exclusionary relationships.
About 5% of pulmonary adenocarcinomas in this cohort of Japanese patients were driven by activated MET by gene amplification or splice mutations. Such patients would be candidates for targeted therapy against MET.
通过基因扩增或突变导致的MET（原癌基因）激活与多种类型的人类癌症有关。对于肺癌，据报道MET基因扩增发生在一部分腺癌中。虽然肺腺癌中MET的体细胞突变很少见，但迄今为止报道的所有突变（只有一个例外）都涉及剪接突变，该突变删除了与c-Cbl E3连接酶结合的近膜结构域；正常情况下，这种结合会导致泛素化和受体降解，而该结构域的缺失会导致MET激活。本研究的目的是阐明MET激活在肺癌发生中的作用。
通过实时定量聚合酶链反应测定187例肺癌患者的MET基因拷贝数，并通过直接测序检测262例患者中删除近膜结构域的MET基因剪接突变。将结果与各种临床和病理特征相关联，包括表皮生长因子受体、KRAS和HER2基因的突变。
所有MET激活的病例均发生在腺癌患者中。MET基因扩增和剪接突变的发生率分别为1.4%（148例中的2例）和3.3%（211例中的7例）。我们鉴定出四种不同的内含子突变，这些突变破坏了基因组DNA中的剪接共有序列。MET激活与表皮生长因子受体、KRAS和HER2基因的突变具有严格的相互排斥关系。
在这组日本患者中，约5%的肺腺癌是由基因扩增或剪接突变导致的MET激活所驱动。这些患者可能是MET靶向治疗的候选者。
