Association of BRCA1 promoter methylation with rs11655505 (c.2265C>T) variants and decreased gene expression in sporadic breast cancer
Association of BRCA1 promoter methylation with rs11655505 (c.2265C>T) variants and decreased gene expression in sporadic breast cancer
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DOI：
10.1007/s12094-012-0968-y
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发表时间：
2013-07-01
影响因子：
3.4
通讯作者：
Syed, Rabbani
中科院分区：
文献类型：
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作者：
Hasan, Tarique N.;Grace, B. Leena;Syed, Rabbani
乳腺癌是全世界妇女最常见的癌症，也是癌症发病率的主要原因，是异常遗传和表观遗传改变的表现。因此，我们的目的是研究BRCA1启动子甲基化与散发乳腺癌中rs11655505 （c - 2265c /T）变异和基因表达的关系。29例散发性乳腺癌组织和26例正常活检用于本研究。从石蜡包埋组织中提取基因组DNA和总RNA，进行SNP分析。亚硫酸氢钠修饰DNA后，通过甲基化特异性PCR检测BRCA1启动子区域的甲基化状态。在所有临床病理参数中，只有雌激素受体-ve和+ve样品的甲基化状态有显著差异（P = 0.04）。基因型（CC、CT和TT）、等位基因频率和甲基化状态与健康对照组无显著差异（P分别为0.67、0.71和0.17）。同样，在不同基因型中，未甲基化的BRCA1启动子与甲基化的启动子在患者和对照组之间没有显著差异。有趣的是，只有BRCA1低表达和正常表达的杂合子（CT）基因型与对照组相比，BRCA1的差异表达有显著差异（P = 0.004）。然而，在肿瘤样本中，基因表达的降低与BRCA1启动子的甲基化状态相关[OR (95% CI) = 25.09 (2.17-29.75)；P = 0.01]。我们的数据表明，在研究人群中，单核苷酸变异rs11655505 （c - 2265c /T）和BRCA1的甲基化状态与散发性乳腺癌的发生没有显著相关性。然而，基因表达的减少与CT基因型和疾病有关。但是，在肿瘤样本中，启动子甲基化与BRCA1基因表达减少的关联表明甲基化可能在基因沉默中起作用。
Breast cancer is the most common cancer and the main cause of cancer morbidity for women worldwide and is manifestation of abnormal genetic as well as epigenetic changes. Therefore, our aim was to study the association of BRCA1 promoter methylation with rs11655505 (c.-2265C/T) variants and gene expression in sporadic breast cancer.Twenty-nine sporadic breast cancer tissues and 26 normal biopsies were used for this study. Genomic DNA and total RNA were extracted from paraffin-embedded tissue and SNP analysis performed. Methylation status of the BRCA1 promoter region was determined by methylation-specific PCR after sodium bisulfite modification of DNA.Among all clinical-pathological parameters only estrogen receptor -ve and +ve samples were significantly different for methylation status (P = 0.04). The genotypic (CC, CT and TT), allelic frequencies and methylation status had not been found to be significantly different from that of healthy controls (P = 0.67, 0.71 and 0.17, respectively). Similarly, methylated BRCA1 promoter was not found to be significantly different in different genotypes from unmethylated promoters between patients and controls. Interestingly, only heterozygous (CT) genotypes with low and normal expression of BRCA1 were significantly different for the differential expression of BRCA1 compared to controls (P = 0.004). However, in tumor samples decreased expression of gene is associated with methylated state of BRCA1 promoter [OR (95 % CI) = 25.09 (2.17-29.75); P = 0.01].Our data suggest that both single nucleotide variations rs11655505 (c.-2265C/T) and the methylation status of BRCA1 are not associated significantly with the occurrence of sporadic breast cancer in studied population. However, decreased expression of gene is associated with the CT genotypes and the disease. But, in case of tumor samples, an association of methylation of the promoter to the decreased expression of BRCA1 gene suggests the possible role of methylation in gene silencing.