Mutation and Polymorphism in the EGFR-TK Domain Associated with Lung Cancer
Mutation and Polymorphism in the EGFR-TK Domain Associated with Lung Cancer
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DOI：
10.1016/s1556-0864(15)30375-0
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发表时间：
2006-09
影响因子：
20.4
通讯作者：
Weiping Zhang;L. Stabile;P. Keohavong;M. Romkes;J. Grandis;A. Traynor;J. Siegfried
中科院分区：
文献类型：
--
作者：
Weiping Zhang;L. Stabile;P. Keohavong;M. Romkes;J. Grandis;A. Traynor;J. Siegfried
BackgroundThe epidermal growth factor receptor (EGFR) is involved in the development and progression of lung cancer. SomaticEGFRmutations are predictors of response to treatment with EGFR tyrosine kinase (TK) inhibitors (TKIs) for lung cancer, especially among never smokers.EGFRmutations may occur independently of other genetic alterations.MethodsThe authors sequenced theEGFR-TK domain and theK-rasandp53genes from lung tumor tissues from 44 never smokers and 46 smokers. A case-control study also was conducted to examine the relationship between anEGFRsingle nucleotide polymorphism in the TK domain and the lung cancer through a multivariate logistic regression analysis. In addition, the authors compared cell growth kinetics, EGFR-TKI sensitivity by MTT, and activation of signaling molecules by immunoblot in lung cancer cell lines with and withoutEGFR-TK mutations.ResultsEGFR-TK mutations were more frequently observed in never smokers (25%) than in smokers (2.2%) (p= 0.001). Excluding cases with aK-rasmutation, the frequency ofEGFR-TK domain mutation was still significantly higher in never smokers than in smokers, 26.2% versus 4.5% (p= 0.046).EGFR-TK mutations andK-rasmutations (p= 0.015), andp53andK-rasmutations (p= 0.015) were mutually exclusive, butp53andEGFR-TK mutations were not (p= 1.00). During sequencing of theEGFR-TK domain in tumors, anEGFRpolymorphism (G2607A) was identified. The genotype AA and AA + AG occurred at a significantly higher frequency in lung cancer cases (n= 122) when compared with controls (n= 147) (odds ratio, 3.39 and 2.67; 95% confidence interval, 1.41–8.17 and 1.17–6.08,p= 0.006 andp= 0.02, respectively). This polymorphism was found independently ofEGFR-TK mutations in lung cancer cases, indicating that it does not predispose to mutations. In vitro, lung cancer cell lines withEGFR-TK mutations also did not containK-rasmutations and displayed a lower growth rate (50%,p= 0.013) thanEGFR-TK wild-type cell lines.EGFR-TK mutant cell lines were more sensitive to both gefitinib and erlotinib, although relative sensitivity to erlotinib compared with wild-type was less pronounced than for gefitinib. Cell lines with a lower growth rate also expressed higher levels of E-cadherin than faster growing cell lines.ConclusionsEGFR-TK mutation frequency is high in never-smoking lung cancer patients and is exclusive of mutation inK-rasbut notp53. In addition to somaticEGFR-TK mutations that arise in lung tumors, germline variation in theEGFR-TK domain might also be associated with an increased risk of lung cancer. SomaticEGFR-TK mutations alter cell biology and response toEGFR-TKIs and may be mutation specific.
