Blackburn Heather L, Ellsworth Darrell L, Shriver Craig D, Ellsworth Rachel E
Windber Research Institute, Windber, PA, 15963, USA.
Cancer Causes Control. 2015 Mar;26(3):319-32. doi: 10.1007/s10552-014-0519-7. Epub 2015 Jan 3.
The cytochrome P450 (CYP) genes are oxygenases involved in estrogen biosynthesis and metabolism, generation of DNA damaging procarcinogens, and response to anti-estrogen therapies. Since lifetime estrogen exposure is an established risk factor for breast cancer, determining the role of CYP genes in breast cancer etiology may provide critical information for understanding tumorigenesis and response to treatment.
This review summarizes literature available in PubMed published between 1993 and 2013 that focuses on studies evaluating the effects of DNA variants in CYP genes on estrogen synthesis, metabolism, and generation of procarcinogens in addition to response to anti-estrogen therapies.
Evaluation of DNA variants in estrogen metabolism genes was largely inconclusive. Meta-analyses of data from CYP19A1 support an association between the number of (TTTA) n repeats in intron 4 and breast cancer risk, but the biological mechanism for this relationship is unknown. Associations between single nucleotide polymorphism in CYP1B1 and DNA damage caused by procarcinogenic estrogen metabolites were ambiguous. Variants in CYP2D6 are associated with altered metabolism tamoxifen; however, current data do not support widespread clinical testing. The effect of variants in CYP19A1 in response to aromatase inhibitors is also questionable.
Evaluation of DNA variants in CYP genes involved with estrogen metabolism or treatment response has been inconclusive, reflecting small samples sizes, tumor heterogeneity, and differences between populations. Better-powered studies that account for genetic backgrounds and tumor phenotypes are thus necessary.
细胞色素P450（CYP）基因是参与雌激素生物合成与代谢、DNA损伤性致癌物生成以及抗雌激素治疗反应的加氧酶。由于终生雌激素暴露是乳腺癌的既定风险因素，确定CYP基因在乳腺癌病因学中的作用可能为理解肿瘤发生和治疗反应提供关键信息。
本综述总结了1993年至2013年发表在PubMed上的文献，这些文献侧重于评估CYP基因中的DNA变异对雌激素合成、代谢、致癌物生成以及抗雌激素治疗反应的影响的研究。
对雌激素代谢基因中DNA变异的评估大多没有定论。对CYP19A1数据的荟萃分析支持内含子4中（TTTA）n重复序列的数量与乳腺癌风险之间存在关联，但这种关系的生物学机制尚不清楚。CYP1B1单核苷酸多态性与致癌性雌激素代谢物引起的DNA损伤之间的关联不明确。CYP2D6中的变异与他莫昔芬代谢改变有关；然而，目前的数据不支持广泛的临床检测。CYP19A1变异对芳香化酶抑制剂反应的影响也存在疑问。
对参与雌激素代谢或治疗反应的CYP基因中DNA变异的评估尚无定论，这反映了样本量小、肿瘤异质性以及人群之间的差异。因此，需要进行更有说服力的研究，考虑遗传背景和肿瘤表型。
