CpG island arrays: An application toward deciphering epigenetic signaturesof breast cancer

CpG island hypermethylation is a frequent epigenetic event in cancer. We ha ve recently developed an array-based method, called differential methylatio n hybridization (DMH), allowing for a genome-wide screening of CpG island h ypermethylation in breast cancer cell lines (T, H-M. Huang et al., Hum. Mol . Genet., 8: 359-470, 1999), In the present study, DMH was applied to scree n 28 paired primary breast tumor and normal samples and to determine whethe r patterns of specific epigenetic alterations correlate with pathological p arameters in the. patients analyzed, Amplicons, representing a pool of meth ylated CpG DNA derived from these samples, were used as hybridization probe s in an array panel containing 1104 CpG island tags. close to 9% of these t ags exhibited extensive hypermethylation in the majority of breast tumors r elative to their normal controls, whereas others had little or no detectabl e changes. Pattern analysis in a subset of CpG island tags revealed that Cp G island hypermethylation is associated with histological grades of breast tumors. Poorly differentiated tumors appeared to exhibit more hypermethylat ed CpG islands than their moderately or well-differentiated counterparts (P = 0.041). This early finding lays the groundwork for a population-based DM H. study and demonstrates the need to develop a database for examining larg e-scale methylation data and for associating specific epigenetic signatures with clinical parameters in breast cancer.