PURPOSE: Epidermal growth factor receptor (EGFR) plays a critical role in signal transduction and is a target for a novel class of anticancer agents that aim to inhibit EGFR-mediated cancer cell growth. Previous studies have demonstrated a dinucleotide (CA)(n) repeat polymorphism in intron 1 of EGFR, ranging from 14 to 21 repeats, that has been suggested to regulate EGFR expression. The longer allele with 21 repeats showed an 80% reduction of gene expression compared with the shorter allele with 16 repeats. Therefore, the evaluation of the allelic distribution of this polymorphism in populations of various ethnic origins will be crucial to understand the interindividual variability in EGFR expression. EXPERIMENTAL DESIGN: We evaluated the influence of ethnicity on this polymorphism by genotyping individuals of Caucasian (n = 183), African-American (n = 84), and Asian (n = 66) background. RESULTS: The frequency of one of the longer alleles, allele 20 is significantly higher in Asian individuals (63% compared with 21% in Caucasians, P = 2 x 10(-18)). In confirmation of prior studies, the shorter allele 16 was the most common allele in Caucasians (43%) and African-Americans (42%), but its frequency was significantly lower in Asians (average 17%, P = 10(-7) compared with Caucasians). CONCLUSION: Major interethnic differences in the allelic frequencies of the EGFR intron 1 polymorphism exist. Our results may contribute to a better understanding of the molecular basis underlying ethnic differences in drug response and may be helpful for future strategies of individualized therapy with EGFR inhibitors.
PURPOSE:Epidermal growth factor receptor (EGFR) plays a critical role in signal transduction and is a target for a novel class of anticancer agents that aim to inhibit EGFR-mediated cancer cell growth. Previous studies have demonstrated a dinucleotide (CA)(n) repeat polymorphism in intron 1 of EGFR, ranging from 14 to 21 repeats, that has been suggested to regulate EGFR expression. The longer allele with 21 repeats showed an 80% reduction of gene expression compared with the shorter allele with 16 repeats. Therefore, the evaluation of the allelic distribution of this polymorphism in populations of various ethnic origins will be crucial to understand the interindividual variability in EGFR expression. EXPERIMENTAL DESIGN: We evaluated the influence of ethnicity on this polymorphism by genotyping individuals of Caucasian (n = 183), African-American (n = 84), and Asian (n = 66) background. RESULTS: The frequency of one of the longer alleles, allele 20 is significantly higher in Asian individuals (63% compared with 21% in Caucasians, P = 2 x 10(-18)). In confirmation of prior studies, the shorter allele 16 was the most common allele in Caucasians (43%) and African-Americans (42%), but its frequency was significantly lower in Asians (average 17%, P = 10(-7) compared with Caucasians). CONCLUSION: Major interethnic differences in the allelic frequencies of the EGFR intron 1 polymorphism exist. Our results may contribute to a better understanding of the molecular basis underlying ethnic differences in drug response and may be helpful for future strategies of individualized therapy with EGFR inhibitors.
Authors: K M Giacomini; C M Brett; R B Altman; N L Benowitz; M E Dolan; D A Flockhart; J A Johnson; D F Hayes; T Klein; R M Krauss; D L Kroetz; H L McLeod; A T Nguyen; M J Ratain; M V Relling; V Reus; D M Roden; C A Schaefer; A R Shuldiner; T Skaar; K Tantisira; R F Tyndale; L Wang; R M Weinshilboum; S T Weiss; I Zineh Journal: Clin Pharmacol Ther Date: 2007-03 Impact factor: 6.875