Building a multigenic model of breast cancer susceptibility: CYP17 and HSD17B1 are two important candidates

We conducted a nested case-control study to evaluate whether polymorphisms in two genes involved in estrogen metabolism, CYP17 and NSD17B1, were usefu l in developing a breast cancer risk model that could help discriminate wom en who are at higher risk of breast cancer, If polymorphisms in these genes affect the level of circulating estrogens, they may directly influence bre ast cancer risk. The base population for this study is a multiethnic cohort study that includes African-American, Non-Latina White, Japanese, Latina, and Native Hawaiian women, For this analysis, 1508 randomly selected contro ls and 850 incident breast cancer cases of the first four ethnic groups who agreed to provide a blood specimen were included (76 and 80% response rate s, respectively). The CYP17 A2 allele and the HSD17B1 A allele were conside red "high-risk" alleles. Subjects were then classified according to number of high-risk alleles, After adjusting for age, weight, and ethnicity, we fo und that carrying one or more high-risk alleles increases the risk of advan ced breast cancer in a dose-response fashion. The risk among women carrying four high-risk alleles was 2.21 [95% confidence interval (CI), 0.98-5.00; P for trend = 0.03] compared with those who carried none. This risk was lar gely limited to women who were not taking hormone replacement therapy (rela tive risk, 2.60; 95% CI, 0.95-7.14) and was most pronounced among those wei ghing 170 pounds or less (RR, 3.05; 95% CI, 1.29-7.25). These findings sugg est that breast cancer risk has a strong genetic: component and supports th e theory that the underlying mechanism of complex traits" can be understood using a multigenic model of candidate genes.