Increased prevalence of EGFR-mutant lung cancer in women and in East Asian populations: analysis of estrogen-related polymorphisms

Bell, D. W., Brannigan, B. W., Matsuo, K., Finkelstein, D. M., Sordella, R., Settleman, J., Mitsudomi, T., Haber, D. A. (July 2008) Increased prevalence of EGFR-mutant lung cancer in women and in East Asian populations: analysis of estrogen-related polymorphisms. Clinical Cancer Research, 14 (13). pp. 4079-84. ISSN 1078-0432

Abstract

PURPOSE: Somatic mutations in the epidermal growth factor receptor (EGFR) gene occur in a subset of non-small-cell lung cancer (NSCLC) and are highly predictive of the clinical response to selective EGFR kinase inhibitors. The prevalence of EGFR-mutant NSCLC is appreciably higher in females than in males and in East Asian than in Caucasian populations. We hypothesized that these disparate frequencies may be attributable to underlying genetic modifiers. Given the coincident differences in sex and ethnic origin, we tested allozymatic variants of enzymes involved in estrogen biosynthesis and metabolism, encoded by polymorphic alleles known to differ in frequency between Caucasian and Asian populations, as modifying alleles. EXPERIMENTAL DESIGN: We genotyped nine polymorphisms in the CYP1A1, CYP17A1, CYP19, HSD17B1, COMT, GSTM1, and GSTT1 genes, in a series of 100 Japanese NSCLCs, selected for equal representation of EGFR wild-type (wt) and EGFR-mutant cases, as well as male and female cases. Associations between polymorphic variants and the EGFR genotype and sex of NSCLC cases were examined using Fisher's exact test of significance. RESULTS: Only CYP1A1 2C showed a difference in allele frequency that approached statistical significance. Heterozygotes were underrepresented among EGFR-mutant cases compared with EGFR-wt cases (27% versus 47%, P = 0.08), with a concurrent trend toward overrepresentation of CYP1A1 2C(Ile/Ile) homozygotes among EGFR-mutant cases as compared with EGFR-wt cases (69% versus 51%, P = 0.13). CONCLUSION: Within the power of this study, our findings suggest that the selected polymorphic variants in the estrogen biosynthesis and metabolism pathways are unlikely to be major genetic modifiers of the prevalence of EGFR-mutant NSCLC.

Item Type:	Paper
Uncontrolled Keywords:	Carcinoma Non-Small Cell Lung epidemiology ethnology genetics metabolism Estrogens metabolism Female Gene Frequency Genotype Heterozygote Humans Lung Neoplasms epidemiology ethnology genetics metabolism Male Mutation Polymorphism Genetic Prevalence Receptor Epidermal Growth Factor genetics metabolism Sex Factors
Subjects:	diseases & disorders > cancer diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > EGFR epidemiology diseases & disorders > cancer > cancer types > lung cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types diseases & disorders > cancer > cancer types
CSHL Authors:	Sordella, Raffaella
Communities:	CSHL labs > Sordella lab
Depositing User:	CSHL Librarian
Date:	1 July 2008
Date Deposited:	07 May 2012 20:58
Last Modified:	13 Mar 2013 15:34
PMCID:	PMC3391698
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/26253

Actions (login required)

Administrator's edit/view item