title: Increased prevalence of EGFR-mutant lung cancer in women and in East Asian populations: analysis of estrogen-related polymorphisms.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Daphne W
authors.initials: DW
authors.lastname: Bell
authors.forename: Brian W
authors.initials: BW
authors.lastname: Brannigan
authors.forename: Keitaro
authors.initials: K
authors.lastname: Matsuo
authors.forename: Dianne M
authors.initials: DM
authors.lastname: Finkelstein
authors.forename: Raffaella
authors.initials: R
authors.lastname: Sordella
authors.forename: Jeff
authors.initials: J
authors.lastname: Settleman
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mitsudomi
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Haber
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000453:epidemiology / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008175:Lung Neoplasms / Q000453:epidemiology / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009154:Mutation; D011110:Polymorphism, Genetic; D015995:Prevalence; D012737:Sex Factors
chemical_list: D004967:Estrogens; D066246:ErbB Receptors