Abstract
Background:Endogenous sex hormones are well-established risk factors for breast cancer; the contribution of specific oestrogen metabolites (EMs) and/or ratios of specific EMs is less clear. We have previously identified a CYP3A7*1C allele that is associated with lower urinary oestrone (E1) levels in premenopausal women. The purpose of this analysis was to determine whether this allele was associated with specific pathway EMs.Methods:We measured successfully 12 EMs in mid-follicular phase urine samples from 30 CYP3A7*1C carriers and 30 non-carriers using HPLC-MS/MS.Results:In addition to having lower urinary E1 levels, CYP3A7*1C carriers had significantly lower levels of four of the 2-hydroxylation pathway EMs that we measured (2-hydroxyestrone, P=1.1 × 10−12; 2-hydroxyestradiol, P=2.7 × 10−7; 2-methoxyestrone, P=1.9 × 10−12; and 2-methoxyestradiol, P=0.0009). By contrast, 16α-hydroxylation pathway EMs were slightly higher in carriers and significantly so for 17-epiestriol (P=0.002).Conclusions:The CYP3A7*1C allele is associated with a lower urinary E1 levels, a more pronounced reduction in 2-hydroxylation pathway EMs and a lower ratio of 2-hydroxylation:16α-hydroxylation EMs in premenopausal women. To further characterise the association between parent oestrogens, EMs and subsequent risk of breast cancer, characterisation of additional genetic variants that influence oestrogen metabolism and large prospective studies of a broad spectrum of EMs will be required.
Highlights
MethodsWe measured successfully 12 EMs in mid-follicular phase urine samples from 30 CYP3A7*1C carriers and 30 non-carriers using HPLC-MS/MS
Endogenous sex hormones are well-established risk factors for breast cancer; the contribution of specific oestrogen metabolites (EMs) and/or ratios of specific EMs is less clear
The CYP3A7*1C allele is associated with a lower urinary E1 levels, a more pronounced reduction in 2-hydroxylation pathway EMs and a lower ratio of 2-hydroxylation:16a-hydroxylation EMs in premenopausal women
Summary
We measured successfully 12 EMs in mid-follicular phase urine samples from 30 CYP3A7*1C carriers and 30 non-carriers using HPLC-MS/MS. The study population from which the women we included in this analysis were drawn has been described previously (Johnson et al, 2012). To maximise the statistical efficiency of this analysis of the CYP3A7*1C allele, which has a minor allele frequency (MAF) of just 4% in Northern European populations (Johnson et al, 2016), we selected 60 women on the basis of genotype; a random sample of 30 CYP3A7*1C carriers and 30 CYP3A7*1C non-carriers. We further selected the two periovulatory samples (samples three and four of the six sequential follicular phase samples) on the basis that oestrogen levels would be at their peak in these samples and this would maximise any differences in levels between CYP3A7*1C carriers and non-carriers. We used the average of these two sequential samples as our outcome variable
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