The CYP3A4*1B polymorphism has no functional significance and is not associated with risk of breast or ovarian cancer
The CYP3A4*1B polymorphism has no functional significance and is not associated with risk of breast or ovarian cancer
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DOI：
10.1097/00008571-200207000-00003
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发表时间：
2002-07-01
期刊：
影响因子：
--
通讯作者：
Liddle, C
中科院分区：
文献类型：
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作者：
Spurdle, AB;Goodwin, B;Liddle, C
CYP3A4 参与内源性类固醇的代谢，而等位基因变体 CYP3A4* 1B 由 5' 侧翼区域内的 A 至 G 多态性组成，称为硝苯地平特异性反应元件 (NFSE)，与高级别和晚期前列腺癌有关。由于已知类固醇激素暴露会影响乳腺癌和卵巢癌的风险，因此我们进行了病例对照研究来评估 CYP3A4* 1B 与乳腺癌或卵巢癌风险之间的关系。 CYP3A4 NFSE 基因型在 951 例乳腺癌病例和 500 例频率与年龄匹配的对照以及 488 例卵巢癌病例和 276 例年龄分布相似的对照中进行了测定。通过无条件逻辑回归进行病例对照分析和基因型分布比较。此外，通过分析瞬时转染至肝源性细胞系和分化良好的大鼠肝细胞原代培养物中的 CYP3A4 报告基因构建体，评估了 CYP3A4* 1B 多态性的功能意义。 GG 基因型在所有组中都很罕见（0-0.4%）。 AG/GG 基因型组合不存在与癌症相关的风险，乳腺癌的 OR (95% CI) 为 0.86 (0.54-1.33) (P= 0.5)，卵巢癌的 OR (95% CI) 为 1.51 (0.80-2.89) (P = 0.2)。 CYP3A4-荧光素酶构建体的分析表明，CYP3A4* 1B 并不始终影响报告基因活性。我们的数据表明 CYP3A4* 1B 多态性与乳腺癌或卵巢癌的风险无关。为了支持这一负面发现，体外功能研究表明 NFSE 基因型不是 CYP3A4 5' 侧翼区域转录活性的关键因素，因此不太可能调节 CYP3A4 介导的类固醇代谢。
CYP3A4 is involved in the metabolism of endogenous steroids, and an allelic variant, CYP3A4* 1B, consisting of an A to G polymorphism within the 5'-flanking region termed the nifedipine-specific response element (NFSE) has been associated with high grade and advanced stage of prostate cancers. Because steroid hormone exposure is known to influence breast and ovarian cancer risk, we conducted case-control studies to assess the relationship between CYP3A4* 1B and risk of breast or ovarian cancer. CYP3A4 NFSE genotype was determined in 951 breast cancer cases and 500 controls frequency matched for age and 488 ovarian cancer cases and 276 controls of similar age distribution. Case-control analyses and comparisons of genotype distributions were conducted by unconditional logistic regression. In addition, the functional significance of the CYP3A4* 1B polymorphism was assessed by analysis of CYP3A4-reporter gene constructs transiently transfected into liver-derived cell lines and primary cultures of well-differentiated rat hepatocytes. The GG genotype was rare in all groups (0-0.4%). There was no risk of cancer associated with the AG/GG genotypes combined, with an OR (95% CI) of 0.86 (0.54-1.33) for breast cancer (P= 0.5), and 1.51 (0.80-2.89) for ovarian cancer (P = 0.2). Analysis of CYP3A4-luciferase constructs showed that CYP3A4* 1B did not consistently affect reporter gene activity. Our data suggest that the CYP3A4* 1B polymorphism is not associated with risk of breast or ovarian cancer. In support of this negative finding, in-vitro functional studies indicate that NFSE genotype is not a critical factor in the transcriptional activity of the CYP3A4 5'-flanking region, and is thus unlikely to modulate CYP3A4-mediated metabolism of steroids.