Increased Prevalence of EGFR -Mutant Lung Cancer in Women and in East Asian Populations: Analysis of Estrogen-Related Polymorphisms

作者：Daphne W. Bell, Brian W. Brannigan, Keitaro Matsuo, Dianne M. Finkelstein, Raffaella Sordella, Jeff Settleman, Tetsuya Mitsudomi, Daniel A. Haber · 发表于：Clinical Cancer Research · 年份：2008 · DOI：10.1158/1078-0432.ccr-07-5030 · 被引用次数：97 · 研究领域：Lung Cancer Treatments and Mutations、Glutathione Transferases and Polymorphisms、Estrogen and related hormone effects

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-...