Abstract
IntroductionDespite similar clinical and pathological features, large numbers of breast cancer patients experience different outcomes of the disease. This, together with the fact that the incidence of breast cancer is growing worldwide, emphasizes an urgent need for identification of new biomarkers for early cancer detection and stratification of patients.MethodsWe used ultrahigh-resolution microarrays to compare genomewide methylation patterns of breast carcinomas (n = 20) and nonmalignant breast tissue (n = 5). Biomarker properties of a subset of discovered differentially methylated regions (DMRs) were validated using methylation-sensitive high-resolution melting (MS-HRM) in a case–control study on a panel of breast carcinomas (n = 275) and non-malignant controls (n = 74).ResultsOn the basis of microarray results, we selected 19 DMRs for large-scale screening of cases and controls. Analysis of the screening results showed that all DMRs tested displayed significant gains of methylation in the cancer tissue compared to the levels in control tissue. Interestingly, we observed two types of locus-specific methylation, with loci undergoing either predominantly full or heterogeneous methylation during carcinogenesis. Almost all tested DMRs (17 of 19) displayed low-level methylation in nonmalignant breast tissue, independently of locus-specific methylation patterns in cases.ConclusionsSpecific loci can undergo either heterogeneous or full methylation during carcinogenesis, and loci hypermethylated in cancer frequently show low-level methylation in nonmalignant tissue.
Highlights
Despite similar clinical and pathological features, large numbers of breast cancer patients experience different outcomes of the disease
The breast cancer incidence has increased since the mid-1980s, and, despite the fact that early detection combined with specialized treatment has significantly improved the survival of cancer patients, the disease still presents a problem for healthcare systems
Identification of hypermethylated loci In the first part of this study, we focused on identification of hypermethylated differentially methylated regions (DMRs) in breast cancer
Summary
Despite similar clinical and pathological features, large numbers of breast cancer patients experience different outcomes of the disease. As well as treatment of any other cancer, can be approached at two levels: first, early detection, which is critical for long-term survival of the patients, and second, personalized patient care, which potentially can become the most successful approach in cancer treatment. Both of these approaches require biomarkers for patient identification and stratification. Global hypomethylation of the cancer genome was initially shown to cause genomewide allelic instability, but recently the involvement of this process in transcriptional gene regulation has become increasingly recognized [2]
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