Heterozygous mutation (G/G→G/A) at nt 2607 of the EGFR gene is closely associated with increases in EGFR copy number and mRNA half life, but impaired EGFR protein synthesis in squamous cell carcinomas of the head and neck – implication for gefitinib efficacy

Nakazaki,Kouichi; Kato,Yasumasa; Taguchi,Takahide; Inayama,Yoshizaki; Ishiguro,Yukari; Kondo,Norio; Horiuchi,Chouichi; Sakakibara,Atuko; Tsukuda,Mamoru

doi:10.3892/ol.2010.188

November-December 2010 Volume 1 Issue 6

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November-December 2010 Volume 1 Issue 6

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Article

Heterozygous mutation (G/G→G/A) at nt 2607 of the EGFR gene is closely associated with increases in EGFR copy number and mRNA half life, but impaired EGFR protein synthesis in squamous cell carcinomas of the head and neck – implication for gefitinib efficacy

Authors:
- Kouichi Nakazaki
- Yasumasa Kato
- Takahide Taguchi
- Yoshizaki Inayama
- Yukari Ishiguro
- Norio Kondo
- Chouichi Horiuchi
- Atuko Sakakibara
- Mamoru Tsukuda
View Affiliations / Copyright

Affiliations: Department of Otorhinolaryngology, Shonan General Hospital, Yokosuka 237-0067, Japan, Department of Oral Function and Molecular Biology, Ohu University School of Dentistry, Tomita-machi, Koriyama 963-8611, Japan, Department of Otorhinolaryngology and Head and Neck Surgery, Yokohama City University School of Medicine, Yokohama 236-0004, Japan, Department of Pathology, Yokohama City University Hospital, Yokohama 236-0004, Japan, Department of Biology and Function in Head and Neck, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
Pages: 1017-1020
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Published online on: September 23, 2010

https://doi.org/10.3892/ol.2010.188
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Abstract

Gefitinib (ZD1839, Iressa®) is an orally active agent that inhibits the tyrosine kinase activity of epidermal growth factor receptor (EGFR). Gefitinib has shown a high efficacy in patients with non-small cell lung carcinoma and specific mutations in the ATP-binding pocket of EGFR. These mutations, however, are extremely rare in squamous cell carcinomas of the head and neck (SCCHN). We previously showed that SCCHN cell lines with a heterozygous mutation (G/G→G/A) at nucleotide 2607 of EGFR are more sensitive to gefitinib than wild-type cell lines (79.5% higher IC50). To determine the relationship between the G/G and G/A genotypes, we assessed the EGFR gene copy number and the EGFR mRNA half-life in 16 different SCCHN cell lines. Fluorescence in situ hybridization showed that the EGFR copy number was significantly higher in the nine 2607G/A cell lines than in the seven 2607G/G cell lines (3.59±2.14 vs. 1.58±0.32 copies, a 2.27-fold difference). Similarly, the half life of EGFR mRNA was 2.24-fold higher in cell lines with the 2607G/A genotype than in those with wild-type. By contrast, the EGFR protein levels were inversely correlated with mRNA abundance. These findings suggest that sensitivity to gefitinib of cells with the heterozygous mutation (2607G/G→G/A) was closely associated with gene amplification, the prolongation of mRNA half-life and a decrease in EGFR protein.

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Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

Heterozygous mutation (G/G→G/A) at nt 2607 of the EGFR gene is closely associated with increases in EGFR copy number and mRNA half life, but impaired EGFR protein synthesis in squamous cell carcinomas of the head and neck – implication for gefitinib efficacy

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