Aberrant CpG-island methylation has non-random and tumour-type-specific patterns

CpG islands frequently contain gene promoters or exons(1) and are usually u nmethylated in normal cells(1-3). Methylation of CPG islands is associated with delayed replication, condensed chromatin and inhibition of transcripti on initiation(4-7). The investigation of aberrant CpG-island methylation in human cancer has primarily taken a candidate gene approach, and has focuse d on less than 15 of the estimated 45,000 CpG islands(8) in the genome. Her e we report a global analysis of the methylation status of 1,184 unselected CpG islands in each of 98 primary human rumours using restriction landmark genomic scanning(9) (RLGS). We estimate that an average of 600 CpG islands (range of 0 to 4,500) of the 45,000 in the genome were aberrantly methylat ed in the rumours, including early stage tumours. We identified patterns of CpG;island methylation that were shared within each tumour type, together with patterns and targets that displayed distinct tumour-type specificity. The expression of many of these genes was reactivated by experimental demet hylation in cultured tumour cells. Thus, the methylation of particular subs ets of CpG islands may have consequences for specific tumour types.