Phase I and phase II enzyme polymorphisms and p53 mutations in breast cancer.

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Breast cancer is the second leading cause of cancer related deaths among American women. It is believed that known risk factors may account for less than half of the cases diagnosed. Some studies suggest that exogenous carcinogens as well as endogenous estrogens may be involved in the initiation of breast cancer. Several of the enzymes involved in the metabolism of these carcinogens have polymorphisms with known functional implications either increasing activation of the compounds or decreasing detoxification. Multiple studies have focused on the association of these genes with risk, often producing conflicting and inconclusive results. Only some of these studies have focused on their association with damage at critical genetic loci, such as the tumor suppressor gene p53. We hypothesize that women with these polymorphisms will be at increased risk for having a mutation in p53. At this point in our ongoing study, 168 Caucasian breast cancer patients have been analyzed for polymorphisms in GSTM1, GSTT1, GSTP1, and CYP1B1 in genomic DNA and p53 mutations in tumor tissue. Approximately 14% of the patients exhibited a mutation at the p53 gene locus. Women with a mutation in p53 were significantly younger than women without a mutation (p=0.048), although they did not differ for other demographic factors. The most interesting trends observed thus far were exhibited with the CYP1B1 A119S allele, which showed that those patients that had at least one serine allele were more likely to have a mutation in p53 [Adjusted odds ratio (OR) = 2.13; 95% Confidence Interval (95% CI) = 0.81-5.58]. Using a recessive model, those patients with the GSTP1 I105V polymorphism were more likely to have a mutation in p53 [OR=1.95; 95%CI= 0.56-6.80]. Both the GSTM1 and GSTP1 A114V polymorphisms appear to have a protective effect [OR=0.61; 95% CI=0.24-1.52 & OR =0.61; 95% CI = 0.13-2.86 respectively]. These associations were not noted for the CYP1B1 L432V and GSTT1 polymorphisms. As these results with a limited sample size are not statistically significant, further analyses with a larger number of patients are required to determine the impact of these polymorphisms on mutations in p53. Patient recruitment into this study is continuing. Overall, we anticipate that this study may help in the identification of women that are at increased risk and therefore would benefit most from early intervention either through chemoprevention or lifestyle modifications. (Supported by NCI grant CA81330 and a grant from the Susan G. Komen Foundation)