Rebbeck Timothy R, Troxel Andrea B, Wang Yiting, Walker Amy H, Panossian Saarene, Gallagher Stephen, Shatalova Ekaterina G, Blanchard Rebecca, Bunin Greta, DeMichele Angela, Rubin Stephen C, Baumgarten Mona, Berlin Michelle, Schinnar Rita, Berlin Jesse A, Strom Brian L
Department of Biostatistics and Epidemiology and Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, 904 Blockley Hall, 423 Guardian Dr., Philadelphia, PA 19104-6021, USA.
J Natl Cancer Inst. 2006 Sep 20;98(18):1311-20. doi: 10.1093/jnci/djj360.
Unopposed estrogen replacement therapy is associated with increased risk of endometrial cancer. To investigate the mechanism of this association, we evaluated whether risk of endometrial cancer was associated with the genotypes involved in steroid hormone metabolism and the duration of exogenous hormone use.
A population-based case-control study in nine counties of the Philadelphia metropolitan area was undertaken with 502 case patients with endometrial cancer and 1326 age- and race-matched control subjects. Data regarding exogenous hormone use were obtained by interview, and genotypes of the genes COMT, CYP1A1, CYP1A2, CYP1B1, CYP3A4, PGR, SULT1A1, SULT1E1, and UGT1A1 were obtained by polymerase chain reaction techniques. Conditional logistic regression was used to examine the relationship among genotype, hormone use, and endometrial cancer risk.
Associations were observed between the risk of endometrial cancer and genotypes of the following steroid hormone metabolism genes: CYP1A12C (adjusted odds ratio [OR] = 1.68, 95% confidence interval [CI] = 1.08 to 2.61); SULT1A13 (adjusted OR = 0.51, 95% CI = 0.29 to 0.92); and the G --> A variant in the promoter of SULT1E1 at position -64 (adjusted OR = 1.45, 95% CI = 1.06 to 1.99). We observed a statistically significant interaction between estrogen replacement therapy use and SULT1A12 genotype: the SULT1A12 allele and long-term use of estrogen replacement therapy were associated with statistically significantly higher risk of endometrial cancer (adjusted OR = 3.85, 95% CI = 1.48 to 10.00) than that of the SULT1A1*2 allele and no estrogen replacement therapy use.
Among women with long-term use of estrogen replacement therapy or combined hormone replacement therapy, the risk of endometrial cancer may be associated with functionally relevant genotypes that regulate steroid hormone sulfation.
无对抗性雌激素替代疗法与子宫内膜癌风险增加相关。为了研究这种关联的机制，我们评估了子宫内膜癌风险是否与参与类固醇激素代谢的基因类型以及外源性激素使用时长有关。
在费城大都市区的九个县开展了一项基于人群的病例对照研究，研究对象包括502例子宫内膜癌患者以及1326名年龄和种族匹配的对照者。通过访谈获取外源性激素使用的数据，并采用聚合酶链反应技术获取COMT、CYP1A1、CYP1A2、CYP1B1、CYP3A4、PGR、SULT1A1、SULT1E1和UGT1A1基因的基因类型。采用条件逻辑回归分析来研究基因类型、激素使用情况与子宫内膜癌风险之间的关系。
观察到子宫内膜癌风险与以下类固醇激素代谢基因的基因类型之间存在关联：CYP1A12C（校正比值比[OR]=1.68，95%置信区间[CI]=1.08至2.61）；SULT1A13（校正OR=0.51，95%CI=0.29至0.92）；以及SULT1E1启动子-64位点的G→A变异（校正OR=1.45，95%CI=1.06至1.99）。我们观察到雌激素替代疗法的使用与SULT1A12基因类型之间存在统计学显著的相互作用：SULT1A12等位基因与长期使用雌激素替代疗法相比，与未使用雌激素替代疗法的SULT1A1*2等位基因相比，子宫内膜癌风险在统计学上显著更高（校正OR=3.85，95%CI=1.48至10.00）。
在长期使用雌激素替代疗法或联合激素替代疗法的女性中，子宫内膜癌风险可能与调节类固醇激素硫酸化的功能相关基因类型有关。
