title: CYP17 promoter polymorphism and breast cancer in Australian women under age forty years.
abstract: BACKGROUND
  The cytochrome P450c17alpha enzyme functions in the steroid biosynthesis pathway, and altered endogenous steroid hormone levels have been reported to be associated with a T to C polymorphism in the 5' promoter region of the CYP17 gene. Because steroid hormone exposure is known to influence breast cancer risk, we conducted a population-based, case-control-family study to assess the relationship between the CYP17 promoter polymorphism and early-onset breast cancer.
  
  
  METHODS
  Case subjects under 40 years of age at diagnosis of a first primary breast cancer, population-sampled control subjects, and the relatives of both case and control subjects were interviewed to record family history of breast cancer and other risk factors. CYP17 genotype was determined in 369 case subjects, 284 control subjects, and 91 relatives of case subjects. Genotype distributions were compared by logistic regression, and cumulative risk was estimated by a modified segregation analysis. All statistical tests were two-tailed.
  
  
  RESULTS
  Compared with the TT genotype (i.e., individuals homozygous for the T allele), the TC genotype was not associated with increased breast cancer risk (P: =.7). Compared with the TT and TC genotypes combined, the CC genotype was associated with a relative risk of 1. 81 (95% confidence interval [CI] = 1.15-2.86; P: =.01) before adjustment for measured risk factors and 1.63 (95% CI = 1.00-2.64; P: =.05) after adjustment. There was an excess of CC genotypes in case subjects who had at least one affected first- or second-degree relative, compared with control subjects unstratified by family history of breast cancer (23% versus 11%; P: =.006), and these case subjects had a threefold to fourfold higher risk than women of other groups defined by genotype and family history of breast cancer. Analysis of breast cancer in first- and second-degree relatives of case subjects with the CC genotype, excluding two known carriers of a deleterious mutation in BRCA1 or BRCA2, gave a relative hazard in women with the CC genotype of 3.48 (95% CI = 1.13-10.74; P: =.04), which is equivalent to a cumulative risk of 16% to age 70 years.
  
  
  CONCLUSIONS
  The CC genotype may modify the effect of other familial risk factors for early-onset breast cancer.
authors.affiliation: Cancer Unit, Joint Experimental Oncology Programme, The Queensland Institute of Medical Research, and The University of Queensland, Brisbane, Australia. mandyS@qimr.edu.au
authors.forename: A B
authors.initials: AB
authors.lastname: Spurdle
authors.forename: J L
authors.initials: JL
authors.lastname: Hopper
authors.forename: G S
authors.initials: GS
authors.lastname: Dite
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.forename: J
authors.initials: J
authors.lastname: Cui
authors.forename: M R
authors.initials: MR
authors.lastname: McCredie
authors.forename: G G
authors.initials: GG
authors.lastname: Giles
authors.forename: M C
authors.initials: MC
authors.lastname: Southey
authors.forename: D J
authors.initials: DJ
authors.lastname: Venter
authors.forename: D F
authors.initials: DF
authors.lastname: Easton
authors.forename: G
authors.initials: G
authors.lastname: Chenevix-Trench
mesh_terms: D000328:Adult; D000367:Age Factors; D017668:Age of Onset; D000483:Alleles; D001315:Australia; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics*; D016022:Case-Control Studies; D017931:DNA Primers; D004273:DNA, Neoplasm / Q000032:analysis; D005260:Female; D019398:Genes, BRCA1 / Q000235:genetics; D016147:Genes, Tumor Suppressor / Q000235:genetics; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D009154:Mutation; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D012306:Risk; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics*
chemical_list: D017931:DNA Primers; D004273:DNA, Neoplasm; D013254:Steroid 17-alpha-Hydroxylase