DNA METHYLATION DIFFERENCES ASSOCIATED WITH TUMOR-TISSUES IDENTIFIED BY GENOME SCANNING ANALYSIS

Most investigations on the role of DNA methylation in cancer have focu sed on epigenetic changes associated with known tumor suppressor genes . This may have led to an underestimation of the number of CPG islands altered by DNA methylation, since it is possible that a subset of unk nown genes relevant to cancer development may preferentially be affect ed by epigenetic rather than genetic means and would not be identified as familial deletions, mutations, or loss of heterozygosity. We used a recently developed screening procedure (methylation-sensitive arbitr arily primed-polymerase chain reaction to scan genomic DNA for CpG: is lands methylated in white blood cells (WBCs) and in tumor tissues. DNA methylation pattern analysis showed little interindividual difference s in the WBCs and normal epithelium (adjacent to colon, bladder, and p rostate cancer cells), but with some tissue-specific differences. Canc er cells showed marked methylation changes that varied considerably be tween different tumors, suggesting variable penetrance of the methylat ion phenotype in patients. Direct sequencing of 8 of 45 bands altered in these cancers showed that several of them were CpG islands, and 2 o f these sequences were identified in GenBank. Surprisingly, three of t he bands studied corresponded to transcribed regions of genes. Thus, h ypermethylation of CpG: islands in cancer cells is not confined to the promoters of growth regulatory genes but is also found in actively tr anscribed regions. (C) 1998 Academic Press.