Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, 630 West 168 St. New York, NY 10032, USA.
Anticancer Res. 2010 Jul;30(7):2489-96.
Promoter hypermethylation and global hypomethylation in the human genome are hallmarks of most cancers. Detection of aberrant methylation in white blood cells (WBC) has been suggested as a marker for cancer development, but has not been extensively investigated. This study was carried out to determine whether aberrant methylation in WBC DNA can be used as a surrogate biomarker for breast cancer risk.
Promoter hypermethylation of 8 tumor suppressor genes (RASSF1A, APC, HIN1, BRCA1, CYCLIND2, RARbeta, CDH1 and TWIST1) and DNA methylation for three repetitive elements (LINE1, Sat2 and Alu) were analyzed in invasive ductal carcinoma of the breast, paired adjacent normal tissue and WBC from 40 breast cancer patients by the MethyLight assay. Methylation in WBC from 40 controls was also analyzed.
Tumor and adjacent tissues showed frequent hypermethylation for all genes tested, while WBC DNA was rarely hypermethylated. For HIN1, RASSF1A, APC and TWIST1, there was agreement between hypermethylation in tumor and adjacent tissues (p=0.04, p=0.02, p=0.005 and p<0.0001, respectively). DNA methylation for the three repetitive elements was lower in tumor compared to adjacent tissue and WBC DNA. Significant correlations in the methylation of Sat2M1 between tumor and adjacent tissues and WBC DNA were found (p<0.0001 and p=0.046, respectively). There was also a significant difference in methylation of Sat2M1 between cases and controls (p=0.01).
These results suggest that further studies of WBC methylation, including prospective studies, may provide biomarkers of breast cancer risk.
人类基因组中启动子的过度甲基化和整体低甲基化是大多数癌症的特征。白细胞（WBC）中异常甲基化的检测已被认为是癌症发展的标志物，但尚未得到广泛研究。本研究旨在确定 WBC DNA 中的异常甲基化是否可用作乳腺癌风险的替代生物标志物。
通过 MethyLight 分析，对 40 例乳腺癌患者的浸润性导管癌、配对的相邻正常组织和 WBC 中的 8 个肿瘤抑制基因（RASSF1A、APC、HIN1、BRCA1、CYCLIND2、RARβ、CDH1 和 TWIST1）的启动子过度甲基化和 3 个重复元件（LINE1、Sat2 和 Alu）的 DNA 甲基化进行了分析。还分析了 40 例对照者的 WBC 甲基化情况。
所有检测基因在肿瘤和相邻组织中均显示频繁的过度甲基化，而 WBC DNA 很少发生过度甲基化。对于 HIN1、RASSF1A、APC 和 TWIST1，肿瘤和相邻组织中的过度甲基化存在一致性（p=0.04、p=0.02、p=0.005 和 p<0.0001）。与肿瘤相比，相邻组织和 WBC DNA 中的三个重复元件的 DNA 甲基化水平较低。在肿瘤与相邻组织和 WBC DNA 之间发现 Sat2M1 的甲基化存在显著相关性（p<0.0001 和 p=0.046）。Sat2M1 的甲基化在病例和对照者之间也存在显著差异（p=0.01）。
这些结果表明，进一步研究 WBC 甲基化，包括前瞻性研究，可能为乳腺癌风险提供生物标志物。
