Associations between Aromatase CYP19 rs10046 Polymorphism and Breast Cancer Risk: From a Case-Control to a Meta-Analysis of 20,098 Subjects

Abstract

Lifetime exposure to estrogen is a factor that plays an important role in the pathogenesis and progression of breast cancer. Genetic variants in genes of the biosynthesis and metabolism of estrogen have been associated with breast cancer risk. Among them, the CYP19 gene encodes for aromatase, the enzyme that catalyzes the conversion of androgens to estrogens. The rs10046 polymorphism on the CYP19 gene has been related to levels of circulating estradiol and to the estradiol/testosterone ratio. To date, epidemiological studies of rs10046 have been performed in different populations with contradictory results. In the present study, we have conducted a case-control analysis (522 cases and 1221 controls) in a Spanish population. Furthermore, we have performed a meta-analysis including 20,098 subjects (7,998 cases and 12,100 controls) to summarize the data available for rs10046 and breast cancer risk. An odds ratio (OR) with a 95% confidence interval (CI) was applied to assess the association. The results of our case-control study show an association between the carriers of at least one C allele (dominant model) and breast cancer risk (OR = 1.29, 95% CI 1.01–1.66, p-value = 0.038). The meta-analysis shows no significant association with breast cancer risk in any of the genetic models tested. The analysis by ethnic subgroups also failed to produce associations. The evaluation of heterogeneity, influence analysis, and publication bias confirms the reliability of the analysis. We can conclude that the rs10046 polymorphism on CYP19 by itself does not constitute breast cancer risk. We cannot, however, reject the possibility that it could contribute (interact), together with other genetic variants, to modify the circulating levels of estradiol.

Analysis of the rs10046 Polymorphism of Aromatase (CYP19) in Premenopausal Onset of Human Breast Cancer

“…A Chinese study provided evidence that the CYP19 rs10046 polymorphism is associated with breast cancer risk among Chinese women [25] and results from a study in a Spanish population also revealed an association between rs10046 and breast cancer risk. In this study, the carriers of at least one C allele had an increased risk of developing breast cancer [26], which is in agreement with other studies, where the frequency of the C allele is higher in cases vs. controls [12,19]. In contrast, Kristensen et al .…”

Genetic Variants in Hormone-Related Genes and Risk of Breast Cancer

“…Circulating estrogen levels were higher among women with 7 base repeat alleles in our study [46] as in most other studies [34], [47]. However, despite the relationship between these SNPs and estrogen levels, most studies, including our own, have not observed any association between these SNPs in CYP19 and UGT1A1 and breast cancer risk [32], [48].…”

Genetic polymorphisms and haplotype of hormone-related genes are associated with the risk of breast cancer in Chinese women

“…Association analysis between rs10046 and BC in different populations showed inconsistent results (Zhang et al, 2009;Pineda et al, 2013). Karin et al (Zins et al, 2014) reported that the TT genotype of this polymorphism was associated with an increased BC risk.…”