Ethnic differences and functional analysis of MET mutations in lung cancer.
Ethnic differences and functional analysis of MET mutations in lung cancer.
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DOI：
10.1158/1078-0432.ccr-09-0070
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发表时间：
2009-09-15
期刊：
影响因子：
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通讯作者：
Salgia R
中科院分区：
文献类型：
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作者：
Krishnaswamy S;Kanteti R;Duke-Cohan JS;Loganathan S;Liu W;Ma PC;Sattler M;Singleton PA;Ramnath N;Innocenti F;Nicolae DL;Ouyang Z;Liang J;Minna J;Kozloff MF;Ferguson MK;Natarajan V;Wang YC;Garcia JG;Vokes EE;Salgia R
与高加索人相比，非裔美国人对肺癌治疗的发病率更高，反应更差。然而，造成显著种族差异的潜在分子机制尚不清楚。本研究检测了肺癌MET基因突变类型和频率的种族差异，并将其与其他频繁突变的基因如表皮生长因子受体(EGFR)、KRAS2和TP53相关联。以141例亚裔、76例高加索人和66例非裔美国人肺癌患者的肿瘤组织基因组DNA为模板，聚合酶链式反应扩增MET和EGFR基因外显子，测序检测突变情况。进一步对突变携带者进行KRAS2和TP53突变筛查。通过分子模拟和肝细胞生长因子结合研究，探索重要MET突变的功能含义。与EGFR中常见的体细胞突变不同，肺肿瘤中的MET突变是胚系突变。MET-N375S是MET最常见的突变，在13%的东亚人中发生，而在非裔美国人中为零。在男性吸烟者和鳞状细胞癌中，MET突变的频率最高。根据肝细胞生长因子配体结合、分子模拟和对MET抑制剂的凋亡易感性的研究，MET-N375S突变似乎赋予了对MET抑制的抵抗力。肺癌组织中的MET在信号素和膜旁区域中存在非同义突变，但在酪氨酸激酶区域中不存在。所有MET突变均为生殖系突变。东亚人、非裔美国人和高加索人有不同的MET基因型和单倍型。信号蛋白结构域的MET突变会影响配基结合。
African Americans have higher incidence and poorer response to lung cancer treatment compared with Caucasians. However, the underlying molecular mechanisms for the significant ethnic difference are not known. The present study examines the ethnic differences in the type and frequency of MET proto-oncogene (MET) mutation in lung cancer and correlated them with other frequently mutated genes such as epidermal growth factor receptor (EGFR), KRAS2, and TP53. Using tumor tissue genomic DNA from 141 Asian, 76 Caucasian, and 66 African American lung cancer patients, exons coding for MET and EGFR were PCR amplified, and mutations were detected by sequencing. Mutation carriers were further screened for KRAS2 and TP53 mutations. Functional implications of important MET mutations were explored by molecular modeling and hepatocyte growth factor binding studies. Unlike the frequently encountered somatic mutations in EGFR, MET mutations in lung tumors were germline. MET-N375S, the most frequent mutation of MET, occurred in 13% of East Asians compared with none in African Americans. The frequency of MET mutations was highest among male smokers and squamous cell carcinoma. The MET-N375S mutation seems to confer resistance to MET inhibition based on hepatocyte growth factor ligand binding, molecular modeling, and apoptotic susceptibility to MET inhibitor studies. MET in lung cancer tissues contained nonsynonymous mutations in the semaphorin and juxtamembrane domains but not in the tyrosine kinase domain. All the MET mutations were germline. East Asians, African-Americans, and Caucasians had different MET genotypes and haplotypes. MET mutations in the semaphorin domain affected ligand binding.