CpG island methylation results in the silencing of the associated gene and is an important step in tumorigenesis. Following a comprehensive isolation of CpG islands that were methylated in human lung adenocarcinoma, we found that in cancer cells de novo CpG island methylation generally occurred in a sporadic manner. However, some methylated CpG islands appeared to cluster in discrete chromosomal regions. In this study, we have investigated the methylation status of CpG islands located at such chromosomal loci. We have found that many CpG islands at the HOXA and HOXD loci were methylated in human lung adenocarcinoma. The de novo methylation of these CpG islands was also observed in patient's DNA from noncancerous portions of lung tissue. These results indicate the presence of speci®c chromosomal regions that are susceptible to de novo methylation.

CpG island methylation is an important mechanism in gene silencing and is a key epigenetic event in cancer development. As yet, the number and identities of the genes that are inactivated in cancer cells has not been determined. In order to address this issue, we have performed a comprehensive isolation of CpG islands that are methylated in human lung adenocarcinomas. We have isolated approximately 200 CpG islands that are methylated in tumor DNA including those of known tumor-associated genes such as the HOXA5 gene. As the library contains the CpG islands of a number of known tumor suppressor genes it is highly likely that additional, previously unidenti®ed tumor suppressor genes, will be present. On average, 1 ± 2% of CpG islands were methylated speci®cally in tumors although this ®gure diered greatly between patients. This study provides an important resource in the search for genes inactivated in tumors and for the investigation of epigenetic dysregulation of gene expression by CpG island methylation.

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We have investigated the methylation status of the repeat unit of the human ribosomal RNA genes in lung cancer. Using a Southern blot analysis approach we have determined that the non-transcribed region of these genes was generally heavily methylated, while the transcribed region was not methylated in either tumor or normal DNA. Our study also revealed that, in one tumor, the boundary of mosaic methylation of the repeat unit was not distinct. In the same tumor, both the non-transcribed ribosomal spacer region and the L1 interspersed repeat sequences became partially demethylated. In tumor cells, the methylation status of DNA can be altered, but the methylation of subtelomeric repeats was found to be maintained. These results suggest that the mosaic methylation of the repeat unit is not necessarily maintained in tumor DNA, while subtelomeric repeats escape tumor-specific wave of demethylation.