Global DNA hypomethylation in breast carcinoma: correlation with prognostic factors and tumor progression.

The global DNA methylation of 136 breast lesions (117 primary invasive carcinomas, 5 benign phyllodes tumors, 11 fibroadenomas, and 3 sclerosing adenosis) and their respective adjacent parenchyma was analyzed using an in vitro enzyme assay. In the group of patients with breast carcinoma, DNA hypomethylation was correlated with clinical and pathologic parameters known to affect disease prognosis. Histopathologic type, disease stage, and tumor grade were evaluated according to the World Health Organization classification, the TNM system, and the criteria of Elston and Ellis' criteria, respectively. DNA flow cytometry was performed in fresh/frozen samples stained with propidium iodide. Hormone receptor (estrogen and progesterone receptor) status was determined by immunocytochemistry. The comparative study of DNA methylation showed that the DNA of breast carcinomas was statistically significantly less methylated than the DNA of the respective adjacent parenchyma (P=0.0001), the DNA of breast benign lesions (P=0.0002), and the DNA of normal parenchyma (P < 0.0001). A statistically significant correlation was found between the global DNA hypomethylation and the disease stage (P=0.0009), tumor size (P=0.0026), and histologic grade (P=0.0097) of malignant neoplasms. A trend for DNA from breast carcinomas with positive axillary lymph nodes (N1) to be more hypomethylated than those without nodal involvement (NO) (P=0.055) was verified. In contrast, no significant association was found between DNA methylation and histologic type of tumors, hormone receptors, DNA ploidy, and S-phase fraction. The current shows that DNA hypomethylation is increased in breast carcinomas, playing a potentially important role in tumor development. These findings also suggest that DNA methylation status may be a biologic marker with prognostic significance in this group of neoplasms.