![]() In a previous study (12, 13), we analyzed 70 HNPCC cases (which met Amsterdam, Modified Amsterdam, HNPCC-like, or Bethesda criteria) for germ-line defects in MSH2, MLH1, and MSH6 genes. One of many such examples is the MMR 3 gene MLH1, where hypermethylation of the MLH1 promoter region is associated with loss of expression and appears to underlie the majority of MMR-defective sporadic cancer cases (8, 9, 10, 11). Consequently, the analysis of DNA cytosine methylation patterns provides an alternative strategy for the study of tumor suppressor gene inactivation in cases where mutations are not observed. Thus, methylation-associated transcriptional silencing is an alternative to mutational inactivation as a cause of loss of tumor suppressor gene function. In the last decade, a number of studies have reported that aberrantly hypermethylated CpG islands are associated with transcriptional silencing of tumor suppressor genes in sporadic cancers (reviewed in Refs. As a consequence, changes in the methylation of CpG-rich regions can result in altered gene expression that is independent of genetic alteration of either coding or regulatory sequences. A number of studies have demonstrated that DNA methylation can directly prevent the binding of transcription factors, such as E2F, cyclic AMP-responsive element binding protein, and USF (4, 5, 6), or act through the binding of methylated CpG-binding proteins to induce chromatin configurations that interfere with the transcription machinery (1, 7). Epigenetic alteration of the human genome can affect cytosine methylation and chromatin structure (1, 2, 3). Approximately 60–90% of CpG dinucleotides are methylated on cytosine in the human genome, although unmethylated GC-rich regions are frequently associated with transcriptionally active genes.
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