Sood Deepti, Johnson Nichola, Jain Pooja, Siskos Alexandros P, Bennett Mark, Gilham Clare, Busana Marta Cecilia, Peto Julian, Dos-Santos-Silva Isabel, Keun Hector C, Fletcher Olivia
Faculty of Medicine, Department of Surgery and Cancer, Imperial College, London SW7 2AZ, UK.
Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, 237 Fulham Road, London SW7 3RP, UK.
Br J Cancer. 2017 Jan;116(3):382-388. doi: 10.1038/bjc.2016.432. Epub 2017 Jan 10.
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 (E) levels in premenopausal women. The purpose of this analysis was to determine whether this allele was associated with specific pathway EMs.
We measured successfully 12 EMs in mid-follicular phase urine samples from 30 CYP3A7*1C carriers and 30 non-carriers using HPLC-MS/MS.
In addition to having lower urinary E 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; 2-hydroxyestradiol, P=2.7 × 10; 2-methoxyestrone, P=1.9 × 10; 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).
The CYP3A7*1C allele is associated with a lower urinary E 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.
内源性性激素是乳腺癌公认的危险因素；特定雌激素代谢物（EMs）和/或特定EMs比例的作用尚不清楚。我们之前已鉴定出一种CYP3A7*1C等位基因，其与绝经前女性较低的尿雌酮（E）水平相关。本分析的目的是确定该等位基因是否与特定途径的EMs相关。
我们使用高效液相色谱-串联质谱法成功测定了30名CYP3A7*1C携带者和30名非携带者卵泡中期尿液样本中的12种EMs。
除尿E水平较低外，CYP3A7*1C携带者所测的2-羟化途径的4种EMs水平也显著较低（2-羟雌酮，P = 1.1×10；2-羟雌二醇，P = 2.7×10；2-甲氧基雌酮，P = 1.9×10；2-甲氧基雌二醇，P = 0.0009）。相比之下，16α-羟化途径的EMs在携带者中略高，17-表雌三醇显著升高（P = 0.002）。
CYP3A7*1C等位基因与绝经前女性较低的尿E水平、2-羟化途径EMs更显著降低以及2-羟化：16α-羟化EMs的较低比例相关。为了进一步明确母体雌激素、EMs与后续乳腺癌风险之间的关联，需要鉴定其他影响雌激素代谢的基因变异，并对广泛的EMs进行大型前瞻性研究。
