HSD17B1 and CYP17 Polymorphisms and Breast Cancer Risk Among Chinese Women in Singapore

Reasons for the recent trend of increasing breast cancer incidence among Chinese and other Asian women are not well understood. Endogenous estrogen levels are strongly associated with breast cancer risk and its determinants include both genetic and lifestyle factors. We conducted a nested case-control study to investigate, within the Singapore Chinese Health Study Cohort, the relationships between polymorphisms in 2 genes involved in estrogen metabolism, CYP17 and HSD17B1, and the risk of breast cancer. For this analysis, 188 incident breast cancer cases and 671 female cohort control subjects were compared. When the HSD17B1 A allele was considered as the "putative high-risk" allele, there was a modest increased risk (adjusted relative risk, RR=1.37, 95% CI=0.90-2.07 for HSD17B1 AA vs. other); this association was statistically significant in analysis restricted to postmenopausal women (RR=1.86, 95% CI=1.14-3.03). There was no significant association between the CYP17 MspAI polymorphism and risk in all subjects (RR=1.06, 95% CI=0.65-1.74 for CYP17 A2A2 vs. CYP17 A1A1) or in postmenopausal women only. When we evaluated breast cancer risk in relation to the joint stratification of CYP17 and HSD17B1 genotypes and according to the combined number of putative high-risk alleles (range, 0-4), we observed an elevated joint effect of the CYP17 and HSD17B1 genes on risk. Women who possessed all 4 putative high-risk alleles of both genes (CYP17 A2A2 and HSD17B1 AA) vs. less displayed a nearly 2-fold increased risk (RR=1.83, 95% CI=0.97-3.44); this finding was statistically significant in postmenopausal women (RR=2.31, 95% CI=1.07-4.98). Risk of breast cancer was similar among women possessing the other genotypes (i.e., less than 4 putative high-risk alleles in the joint CYP17/HSD17B1 genotypes). In addition, the significant increased risk of breast cancer associated with nulliparity or late age at first live birth (age 31 years or older) was largely limited to women with the high-risk CYP17 A1A2/A2A2 or HSD17B1 AA genotypes (RR=2.41, 95% CI=1.56-3.72; RR=4.39, 95% CI=1.71-11.30, respectively). The latter gene-parity effects were especially pronounced in postmenopausal women.