Detection Of Epigenetic Change

DNA methylation at CpG dinucleotides in the promoter region of many genes is commonly associated with transcriptional gene silencing. Gene hypermethylation is therefore another mechanism for inactivation of tumor-suppressor genes,53 and has been shown to be a frequent and early alteration in many tumor types, including breast cancers.54-56 Hence, early methylation changes might prove to be useful markers for cancer screening if they are also tumor specific. A number of tumor-suppressor genes, including RAS-associated domain family protein 1A (RASSFla)57 and adenomatous polyposis coli (APC),58 have been shown to be hypermethylated in breast cancers but unmethy-lated in normal cells, and these and other targets are currently being studied as potential cancer-specific biomarkers in both serum and plasma.

Thus far, there have been five studies published, which have examined promoter hyper-methylation in paired tumor and serum, or plasma DNA from breast cancer patients using PCR-based approaches (summarized in Table 8.2). In total, 12 different loci have been investigated, with p16, APC, and RASSFla common to more than one study.59-63 Using just two markers, p16 and CDH1, Hu et al59 were first to demonstrate common methylation in plasma and tumor DNA for 9 of 36 (25%) breast cancers.59 Moreover, the other 25 cases without methylation in tumor DNA did not show any epigenetic change in plasma. Tumor suppressor promoter hypermethylation was then detected in preinvasive DCIS.60 However, the study also detected methylation in a small proportion (13%) of the 76 female controls studied, suggesting that the particular methyla-tion events were not tumor specific. Recently, Sharma et al63 reported high sensitivity and demonstrated concordant hypermethylation between tumor and serum DNA for 30 of 36 (83%) breast cancers. These studies hold some promise for methylation-based cancer screening and monitoring. However, issues remain to be resolved in terms of assay sensitivity and specificity, and additional studies are needed to fully validate hypermethylation-based screening in a larger number of cases and to examine HR populations.

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