CYP17 promoter polymorphism and breast cancer in Australian women under age forty years

Background: The cytochrome P450c17 alpha enzyme functions in the steroid bi osynthesis pathway, and altered endogenous steroid hormone levels have been reported to be associated with a T to C polymorphism in the 5' promoter re gion of the CYP17 gene. Because steroid hormone exposure is known to influe nce breast cancer risk, we conducted a population-based, case control-famil y 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 intervie wed 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 logist ic 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 genoty pe 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 subj ects who had at Least one affected first- or second-degree relative, compar ed with control subjects unstratified by family history of breast cancer (2 3% versus 11%; P = .006), and these case subjects had a threefold to fourfo ld higher risk than women of other groups defined by genotype and family hi story of breast cancer. Analysis of breast cancer in first- and second-degr ee relatives of case subjects with the CC genotype, excluding two known car riers of a deleterious mutation in BRCA1 or BRCA2, gave a relative hazard i n 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.