Aberrant methylation of genes in low-grade astrocytomas.

The underlying basis of the malignant progression of astrocytomas is a specific and cumulative series of genetic alterations, most of which are confined to high-grade tumors. In contrast, a proportion of low-grade astrocytomas have a relatively normal-appearing genome when examined with standard genetic screening methods. These methods do not detect epigenetic events such as aberrant methylation of CpG island, which result in transcriptional silencing of important cancer genes. To determine if aberrant methylation is involved in the early stages of astrocytoma development, we assessed the methylation status of 1,184 genes in each of 14 low-grade astrocytomas using restriction landmark genome scanning (RLGS). The results showed nonrandom and astrocytoma-specific patterns of aberrantly methylated genes. We estimate that an average of 1,544 CpG island-associated genes (range, 38 to 3,731) of the approximately 45,000 in the genome are aberrantly methylated in each tumor. Expression of a significant proportion of the genes could be reactivated by 5-aza-2-deoxycytidine-induced demethylation in cultured glioma cell lines. The data suggest that aberrant methylation of genes is more prevalent than genetic alterations and may have consequences for the development of low-grade astrocytomas.