Intron 1 Polymorphism, Mutation and the Protein Expression of Epidermal Growth Factor Receptor in Relation to the Gefitinib Sensitivity of Korean Lung Cancer Patients
2
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
Background : Epidermal growth factor receptor (EGFR) intron 1 polymorphism in non-small cell lung cancer (NSCLC) has been found to have therapeutic implications for the patients treated with EGFR tyrosine kinase inhibitors. However, its clinical significance as related to gefitinib responsiveness is still controversial. We examined CA repeat polymorphism in intron 1 of the EGFR gene and its relation with the EGFR gene mutation in NSCLC patients who were treated with gefitinib. Methods : Sixty seven patients who were treated with gefitinib were analyzed for intron 1 polymorphism in the EGFR gene, the EGFR mutations and the EGFR protein expression. Two hundred twenty seven samples of NSCLC were analyzed for EGFR mutations. Results : CA repeat was low in 27 patients (40.3%) and high in 40 (59.7%) patients. The response rate for gefitinib therapy was higher in the patient population with a low number of CA repeats in the EGFR gene (p=0.047) and in the patients with the mutated type of EGFR (p= 0.048), though these two factors were not related. Thirty four patients (15.0%) harbored EGFR mutations. Conclusions : This study suggests that the intron 1 CA repeat polymorphism of the EGFR gene may serve as a predictor of the clinical outcome of NSCLC patients treated with gefitinib, and this without regard for EGFR mutation. Our data further supports the importance of EGFR mutations with regard to a distinct clinical profile and the prognostic implications for NSCLC patients.
Abstract
Background : Epidermal growth factor receptor (EGFR) intron 1 polymorphism in non-small cell lung cancer (NSCLC) has been found to have therapeutic implications for the patients treated with EGFR tyrosine kinase inhibitors. However, its clinical significance as related to gefitinib responsiveness is still controversial. We examined CA repeat polymorphism in intron 1 of the EGFR gene and its relation with the EGFR gene mutation in NSCLC patients who were treated with gefitinib. Methods : Sixty seven patients who were treated with gefitinib were analyzed for intron 1 polymorphism in the EGFR gene, the EGFR mutations and the EGFR protein expression. Two hundred twenty seven samples of NSCLC were analyzed for EGFR mutations. Results : CA repeat was low in 27 patients (40.3%) and high in 40 (59.7%) patients. The response rate for gefitinib therapy was higher in the patient population with a low number of CA repeats in the EGFR gene (p=0.047) and in the patients with the mutated type of EGFR (p= 0.048), though these two factors were not related. Thirty four patients (15.0%) harbored EGFR mutations. Conclusions : This study suggests that the intron 1 CA repeat polymorphism of the EGFR gene may serve as a predictor of the clinical outcome of NSCLC patients treated with gefitinib, and this without regard for EGFR mutation. Our data further supports the importance of EGFR mutations with regard to a distinct clinical profile and the prognostic implications for NSCLC patients.
참고문헌 (29)
- Paez JG, "EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy", Science, 304, pp.1497~1500 (2004)
- Lynch TJ, "Activating mutations in the epidermal growth factor receptor underlying responsiveness of nonsmall cell lung cancer to gefitinib", N Engl J Med, 350, pp.2129~2139 (2004)
- Ranson M, "ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of phase I trial", J Clin Oncol, 20, pp.2240~2250 (2002)
- Fukuoka M, "Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small cell lung cancer", J Clin Oncol, 21, pp.2237~2246 (2003)
- Miller VA, "Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in ad-vanced non-small-cell lung cancer (NSCLC)", J Cilin Oncol, 22, pp.1103~1109 (2004)
- Pao W, "EGF receptor gene mutations are common in lung cancer from never smokers and are associated with sensitivity of tumor to gefitinib and erlotinib", Proc Natl Acad Sci, pp.13306~13311 (2004)
- Han SH, "Predictive and prognostic impact of epidermal growth factor receptor mutation in non-small-cell lung cancer patients treated with gefitinib", J Clin Oncol, 23, pp.1~9 (2005)
- Huang SF, "High frequency of epidermal growth factor receptor mutations with complex patterns in non-small cell lung cancers related to gefitinib responsiveness in Taiwan", Clin Cancer Res, 10, pp.8195~8203 (2004)
- Henrion D, "Angiotensin II type 1 receptor gene polymorphism is associated with an increased vascular reactivity in the human mammary artery in vitro", J Vasc Res, 35, pp.356~362 (1998)
- Tidow N, "Distinct amplification of an untranslated regulatory sequence in the EGFR gene contributes to early steps in breast cancer development", Cancer Res, 63, pp.1172~1178 (2003)
- Buerger H, "Allelic length of a CA dinucleotide repeat in EGFR gene correlates with the frequency of amplification of this sequence-first results of an interethnic breast cancer study", J Pathol, 203, pp.545~550 (2004)
- Amador ML, "An epidermal growth factor receptor intron I polymorphism mediates response to epidermal growth factor receptor inhibitors", Cancer Res, 64, pp.9139~9143 (2004)
- Therasse P, "New guideline to evaluate the response to treatment in solid tumors", J Natl Cancer Inst, 92, pp.205~216 (2000)
- Shigematsu H, "Clinical and biological features associated with epidermal growth factor receptor mutations in lung cancers", J Natl Cancer Inst, 97, pp.339~346 (2005)
- Lee SJ, "No association between dinucleotide repeat polymorphism in intron 1 of the epidermal growth factor receptor gene EGFR and risk of lung cancer", Cancer Genet Cytogenet, 172, pp.29~32 (2007)
- Han SW, "Intron 1 CA dinucleotide repeat polymorphism and mutations of epidermal growth factor receptor and gefinitib responsiveness in non-small cell lung cancer", Pharmacogenet Genomics, 17, pp.313~319 (2007)
- Liu W, "Interethnic difference in the allelic distribution of human epidermal growth factor receptor intron 1 polymorphism", Clin Cancer Res, 9, pp.1009~1012 (2003)
- Nie Q, "The epidermal growth factor receptor intron 1 (CA) microsatellite polymorphism is a potential predictor of treatment outcome in patients with advanced lung cancer treated with gefitinib", Eur J Pharmacol, 10, pp.1~7 (2007)
- Sueoka-Aragane N, "Exon 19 of EGFR mutation in relation to CA-repeat polymorphism in intron 1", Cancer Sci, 99, pp.1180~1187 (2008)
- Buerger H, "Length and loss of heterozygosityo f an intron 1 polymorphic sequence of EGFR is related to cytogenetic alteration and epithelial growth factor receptor expression", Cancer Res, 60, pp.854~857 (2000)
- Nomura M, "Polymorphism, mutations and amplification of the EGFR gene in non-small cell lung cancers", PLoS Medicine, 4, pp.715~727 (2007)
- Etienne-grimaldi MC, "Analysis of the dinucleotide repeat polymorphism in the EGFR gene in head and neck cancer patients", Ann Oncol, 16, pp.934~941 (2005)
- Cappuzo F, "Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small cell lung cancer", J Natl Cancer Inst, 97, pp.643~655 (2005)
- Prudkin L, "Epidermal growth factor receptor abnormalities in lung cancer. Pathogenetic and clinical implications", Ann Diag Pathol, 10, pp.306~315 (2006)
- Sone T, "Comparative analysis of epidermal growth factor receptor mutations and gene amplification as predictors of gefitinib efficacy in Japanese patients with nonsmall cell lung cancer", Cancer, 109, pp.1836~1844 (2007)
- Pao W, "KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erotinib", PLoS Med, 2, pp.e17~ (2005)
- Hirsch FR, "Epidermal growth factor receptor in non-small cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis", J Clin Oncol, 21, pp.3798~3807 (2003)
- Gebhardt F, "Modulation of epidermal growth factor receptor gene transcription by a polymorphic dinucleotide repeat in intron 1", J Biol Chem, 274, pp.13176~13180 (1999)
- Parra HS, "Analysis of epidermal growth factor receptor expression as a predictive factor expression for response to gefitinib (“Irresa”, ZD1839) in non-small-cell lung cancer", Br J Cancer, 91, pp.208~212 (2004)