Mutation and polymorphism in the EGFR-TK domain associated with lung cancer.

Mutation and polymorphism in the EGFR-TK domain associated with lung cancer. Research Abstract Details 

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Mutation and polymorphism in the EGFR-TK domain associated with lung cancer. Abstract Text:

Weiping Zhang,Laura P Stabile,Phouthone Keohavong,Marjorie Romkes,Jennifer R Grandis,Anne M Traynor,Jill M Siegfried,

BACKGROUND: The epidermal growth factor receptor (EGFR) is involved in the development and progression of lung cancer. Somatic EGFR mutations are predictors of response to treatment with EGFR tyrosine kinase (TK) inhibitors (TKIs) for lung cancer, especially among never smokers. EGFR mutations may occur independently of other genetic alterations. METHODS: The authors sequenced the EGFR-TK domain and the K-ras and p53 genes from lung tumor tissues from 44 never smokers and 46 smokers. A case-control study also was conducted to examine the relationship between an EGFR single 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 without EGFR-TK mutations. RESULTS: EGFR-TK mutations were more frequently observed in never smokers (25%) than in smokers (2.2%) (p = 0.001). Excluding cases with a K-ras mutation, the frequency of EGFR-TK domain mutation was still significantly higher in never smokers than in smokers, 26.2% versus 4.5% (p = 0.046). EGFR-TK mutations and K-ras mutations (p = 0.015), and p53 and K-ras mutations (p = 0.015) were mutually exclusive, but p53 and EGFR-TK mutations were not (p = 1.00). During sequencing of the EGFR-TK domain in tumors, an EGFR polymorphism (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 and p = 0.02, respectively). This polymorphism was found independently of EGFR-TK mutations in lung cancer cases, indicating that it does not predispose to mutations. In vitro, lung cancer cell lines with EGFR-TK mutations also did not contain K-ras mutations and displayed a lower growth rate (50%, p = 0.013) than EGFR-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. CONCLUSIONS: EGFR-TK mutation frequency is high in never-smoking lung cancer patients and is exclusive of mutation in K-ras but not p53. In addition to somatic EGFR-TK mutations that arise in lung tumors, germline variation in the EGFR-TK domain might also be associated with an increased risk of lung cancer. Somatic EGFR-TK mutations alter cell biology and response to EGFR-TKIs and may be mutation specific.

Mutation and polymorphism in the EGFR-TK domain associated with lung cancer. Publishing Authors By Initials

W Zhang,LP Stabile,P Keohavong,M Romkes,JR Grandis,AM Traynor,JM Siegfried,

For similar behavior and behavior mechanisms: behavior: habits: smoking research abstracts see: behavior and behavior mechanisms: behavior: habits: smoking research

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MEDLINE DATE:

Mutation and polymorphism in the EGFR-TK domain associated with lung cancer. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Journal of thoracic oncology : official publicatio

VOLUME: 1

Page Numbers: 635-47

Journal Abbreviation:

ISSN: 1556-1380

DAY: 3

MONTH: Sep

YEAR: 2006

Mutation and polymorphism in the EGFR-TK domain associated with lung cancer. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 101274235

Mutation and polymorphism in the EGFR-TK domain associated with lung cancer. Keywords Mesh Terms:

KEYWORDS: Smoking

MESH TERMS: genetics

Chemical & Substance for Abstract: Mutation and polymorphism in the EGFR-TK domain associated with lung cancer. Information

Substance Name: Receptor, Epidermal Growth Factor

Registry Number: EC 2.7.1.112

Grant and Affiliation Information for Mutation and polymorphism in the EGFR-TK domain associated with lung cancer.

AFFILIATION: Department of Pharmacology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213-1863, USA.

Country: United States

AGENCY: United States NCI

GRANT: CA9045440

ACRONYM: CA

MEDLINETA: J Thorac Oncol

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