Mancini D N, Rodenhiser D I, Ainsworth P J, O'Malley F P, Singh S M, Xing W, Archer T K
London Health Sciences Centre, Department of Paediatrics at the University of Western Ontario, Canada.
Oncogene. 1998 Mar 5;16(9):1161-9. doi: 10.1038/sj.onc.1201630.
Breast cancer is a genetic disease arising from a series of germ-line and/or somatic DNA changes in a variety of genes, including BRCA1 and BRCA2. DNA modifications have been shown to occur by a number of mechanisms that include DNA methylation. In some cases, the aberrant methylation of CpGs within 5' regulatory regions has led to suppression of gene activity. In this report we describe a variation in the pattern of DNA methylation within the regulatory region of the BRCA1 gene. We found no evidence of methylation at CpGs within the BRCA1 promoter in a variety of normal human tissues. However, screening of a series of randomly sampled breast carcinomas revealed the presence of CpG methylation adjacent to the BRCA1 transcription start site. One such methylated CpG occurs at a putative CREB (cAMP-responsive element binding) transcription factor binding site in the BRCA1 promoter. Gelshift assays with methylated and unmethylated BRCA1/CREB binding site oligonucleotides demonstrate that this site is sensitive to site-specific CpG methylation. These data suggest that aberrant DNA methylation at regulatory sequences in the BRCA1 locus may play a role in the transcriptional inactivation of the BRCA1 gene within subclones of breast tumors. This study represents the first evidence suggesting a role for DNA methylation in the transcriptional inactivation of the BRCA1 in human breast cancer.
乳腺癌是一种遗传性疾病，由包括BRCA1和BRCA2在内的多种基因中的一系列种系和/或体细胞DNA变化引起。DNA修饰已被证明可通过多种机制发生，包括DNA甲基化。在某些情况下，5'调控区域内CpG的异常甲基化导致基因活性受到抑制。在本报告中，我们描述了BRCA1基因调控区域内DNA甲基化模式的一种变化。我们在多种正常人体组织中未发现BRCA1启动子内CpG甲基化的证据。然而，对一系列随机抽样的乳腺癌进行筛查发现，在BRCA1转录起始位点附近存在CpG甲基化。其中一个这样的甲基化CpG出现在BRCA1启动子中一个假定的CREB（cAMP反应元件结合）转录因子结合位点处。用甲基化和未甲基化的BRCA1/CREB结合位点寡核苷酸进行凝胶迁移分析表明，该位点对位点特异性CpG甲基化敏感。这些数据表明，BRCA1基因座调控序列处的异常DNA甲基化可能在乳腺肿瘤亚克隆中BRCA1基因的转录失活中起作用。这项研究首次证明了DNA甲基化在人类乳腺癌中BRCA1转录失活中的作用。
