Nonrandom distribution of aberrant promoter methylation of cancer-related genes in sporadic breast tumors
Nonrandom distribution of aberrant promoter methylation of cancer-related genes in sporadic breast tumors
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DOI：
10.1158/1078-0432.ccr-04-0555
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发表时间：
2004-08-15
影响因子：
11.5
通讯作者：
Fazio, VM
中科院分区：
文献类型：
--
作者：
Parrella, P;Poeta, ML;Fazio, VM
目的：为了进一步确定散发性乳腺癌中 CpG 岛高甲基化的整体模式，我们在 54 个原发性乳腺癌和 10 个乳腺良性病变中的 10 个基因位点搜索了异常启动子甲基化。实验设计：从良性和恶性组织转化的基因组 DNA 硫酸氢钠用作 BRCA1、p16、p16 的甲基特异性 PCR 的模板。 ESR1、GSTbeta1、TRbeta1、RARbeta2、HIC1、APC、CCND2 和 CDH1 基因。结果：大多数乳腺癌 (85%) 至少在 1 个测试基因座中显示出异常甲基化，其中一半显示 3 个或更多甲基化基因。发现异常启动子甲基化频率最高的是 HIC1 (48%)，其次是 ESR1 (46%) 和 CDH1 (39%)。除 CDH1 基因外，在乳腺良性病变中检测到类似的甲基化频率（P = 0.02）。甲基化分布分析表明，ESR1 启动子的甲基化与 CDH1、TRP1、GSTP1 和 CCND2 位点的甲基化之间存在统计学显着相关性 (P < 0.03)。 BRCA1 启动子的甲基化状态与 RARbeta2 位点的甲基化呈负相关 (P < 0.03)。结论：我们的结果表明，散发性乳腺癌中启动子高甲基化呈非随机分布，肿瘤亚群的特征是特定癌症相关基因的异常甲基化。这些乳腺癌亚组可能代表不同的生物实体，在治疗敏感性、转移发生和总体预后方面存在潜在差异。
Purpose: In an effort to additionally determine the global patterns of CpG island hypermethylation in sporadic breast cancer, we searched for aberrant promoter methylation at 10 gene loci in 54 primary breast cancer and 10 breast benign lesions.Experimental Design: Genomic DNA sodium bisulfate converted from benign and malignant tissues was used as template in methyl-specific PCR for BRCA1, p16, ESR1, GSTbeta1, TRbeta1, RARbeta2, HIC1, APC, CCND2, and CDH1 genes.Results: The majority of the breast cancer (85%) showed aberrant methylation in at least I of the loci tested with half of them displaying 3 or more methylated genes. The highest frequency of aberrant promoter methylation was found for HIC1 (48%) followed by ESR1 (46%), and CDH1 (39%). Similar methylation frequencies were detected for breast benign lesions with the exception of the CDH1 gene (P = 0.02). The analysis of methyllation distribution indicates a statistically significant association between methylation of the ESR1 promoter, and methylation at CDH1, TRP1, GSTP1, and CCND2 loci (P < 0.03). Methylated status of the BRCA1 promoter was inversely correlated with methyllation at the RARbeta2 locus (P < 0.03).Conclusions: Our results suggest a nonrandom distribution for promoter hypermethylation in sporadic breast cancer, with tumor subsets characterized by aberrant methylation of specific cancer-related genes. These breast cancer subgroups may represent separate biological entities with potential differences in sensitivity to therapy, occurrence of metastasis, and overall prognosis.