SULT1A1 and SULT1E1 genetic polymorphism are associated with the risk and survival of breast cancer Free

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Human sulfotransferase (SULT) isoforms catalyze the sulfation of estrogen; SULT1E1 has the lowest K_m values for estrogens of the 10 known human SULT isoforms and SULT1A1 has broad substrate of phenolic and estrogenic compound primarily expressed in breast tumors. We hypothesized that genetic polymorphisms in SULT1A1 and SULT1E1 genes might influence the risk and the survival of breast cancer. Histologically confirmed sporadic breast cancer patients (n=920) and controls (n=1154) without present or previous history of cancer were recruited from several teaching hospitals in Seoul during 1995-2003. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by logistic regression model adjusting for age, parity, age at first full term pregnancy, and BMI. In survival analysis, Kaplan-Meier method were used and Hazard ratios (HRs) were calculated with Cox proportional hazard model adjusted for age, parity, age at first full term pregnancy, BMI and TMN stages for 283 breast cancer patients with completed treatments. Among known polymorphisms of SULT1A1 and SULT1E1, those of which the variant allele frequencies are more than 10% were selected for evaluation. Genetic polymorphisms of SULT1A1 c.638G>A (rs1042028, R213H) and SULT1E1 c.949G>A (rs3786599), IVS1-447C>A (rs3775778), IVS4-1653T>C (rs3775775) were determined by 5’-nuclease assay (TaqMan). SULT1A1 c.638A allele frequency (9.7%) is much lower than those in Caucasian (35%). Allele frequencies of SULT1E1 are c.949A: 29.4%, IVS1-447A: 22.8% and IVS4-1653C: 7.5% in controls, respectively. These SULT1E1 alleles were found to be in linkage disequilibrium (p<0.001); the most common haplotype was G-C-T in both cases (49.8%) and controls (47.4%). The overall haplotype, however, did not significantly different between two groups (p=0.484). Women with SULT1E1 c.949 GG genotype moderately but significantly increased the breast cancer risk compared to those with GA or AA genotypes (OR=1.2, 95% CI=1.03-1.47). There was no significant association between genotypes of SULT1A1 and other SULT1E1 and breast cancer risk. Patients with SULT1E1 IVS4-1653 TC or CC genotypes showed approximately 4-fold increased risk of recurrence (HR=4.3, 95% CI=1.69-10.76) compared to those with TT genotype. These findings suggest that genetic polymorphisms of SULT1E1 are associated with increased risk and also related to overall survival of breast cancer in Korean women.