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首页> 外文期刊>British Journal of Cancer >MGMT promoter hypermethylation and K-RAS, PTEN and TP53 mutations in tamoxifen-exposed and non-exposed endometrial cancer cases
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MGMT promoter hypermethylation and K-RAS, PTEN and TP53 mutations in tamoxifen-exposed and non-exposed endometrial cancer cases

机译：他莫昔芬暴露和未暴露子宫内膜癌病例中的MGMT启动子过度甲基化和K-RAS，PTEN和TP53突变

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Background: Tamoxifen has anti-oestrogenic and anti-tumour activity in the breast, but is oestrogenic and carcinogenic in the endometrium. It can induce experimental tumours by both hormonal and DNA-damaging mechanisms, but its carcinogenic mode of action in human endometrium remains unclear.Methods: We investigated whether an epigenetic mechanism, involving promoter hypermethylation of the gene for the DNA repair enzyme MGMT (O6-methylguanine DNA methyltransferase), was associated with K-RAS, TP53 and PTEN mutations in endometrial tumours from women treated with tamoxifen (TAM, n =30) or unexposed to the drug (EC, n =38).Results: There were significant ( P <0.05) differences in tumour grade between the TAM and EC groups, with more favourable morphology in the latter. K-RAS mutations, predominantly G>A, occurred in small numbers in both groups. TP53 mutations were of mainly A>G, C>T and indel modifications in both groups, but more frequent in TAM cases. PTEN mutations dominated in EC tumours and were of the type that has large impact on protein function, such as indel or nonsense mutations. These observations alongside the mutational spectrum in PTEN suggest that the malignancies arise from different backgrounds, hence pointing to an effect of tamoxifen. Both groups displayed MGMT promoter hypermethylation. This coincided with mutations more frequently in the TAM (78%) than in the EC (50%) group, even though there were significantly ( P <0.05) fewer mutations and methylations in TAM cases.Conclusions: Although the difference in coincidence did not reach significance with the current sample size, the findings suggest that epigenetic processes may play a role in the way tamoxifen induces endometrial cancer.
机译：背景：他莫昔芬在乳房中具有抗雌激素和抗肿瘤活性，但在子宫内膜中具有雌激素和致癌作用。它可以通过激素和DNA损伤机制诱导实验性肿瘤，但其在人子宫内膜的致癌作用方式尚不清楚。方法：我们研究了表观遗传机制是否涉及DNA修复酶MGMT（O6-甲基鸟嘌呤DNA甲基转移酶）与他莫昔芬（TAM，n = 30）或未暴露于药物（EC，n = 38）的妇女子宫内膜肿瘤中的K-RAS，TP53和PTEN突变有关。 P <0.05）TAM和EC组之间肿瘤分级的差异，后者的形态更有利。两组中均少量发生K-RAS突变，主要是G> A。 TP53突变在两组中主要是A> G，C> T和插入缺失修饰，但在TAM病例中更频繁。 PTEN突变在EC肿瘤中占主导地位，并且是对蛋白质功能产生重大影响的类型，例如indel或无意义突变。这些观察结果以及PTEN中的突变谱表明，恶性肿瘤来自不同的背景，因此表明了他莫昔芬的作用。两组均显示MGMT启动子高甲基化。尽管TAM病例中的突变和甲基化明显减少（P <0.05），但TAM中突变的发生率（78％）比EC（50％）的发生率高。在当前样本量下达到显着性，该发现表明表观遗传过程可能在他莫昔芬诱导子宫内膜癌的方式中起作用。

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