Epigenetics Changes in Cancer Cells

Highlights of the American Association for Cancer Research Special Conference on Chromatin, Chromosomes, and Cancer Epigenetics; November 10-14, 2004; Waikoloa, Hawaii

Kris Novak, PhD

In This Article

Genomewide Methylation Patterns

Although methylation changes in certain genes are associated with specific cancer types, little is known about the extent to which methylation changes occur in cancer cells: Do changes occur just in specific genes or throughout large regions of chromosomes? Susan Clark,[10] of the Sydney Cancer Center, Sydney, Australia, and colleagues are using a technique called amplification of intermethylated sites (AIMS) to study genomewide levels of methylation and gene silencing in different cell types. In analyzing methylated chromosome sequences in 98 human colorectal cancer samples, her group identified a locus at chromosome 2q14.2 that is hypomethylated in normal tissue samples but hypermethylated in tumor-cell samples.

In the cancer cells, such epigenetic alteration was not just restricted to CpG islands within that region. The increase in methylation spanned multiple and contiguous CpG islands in the chromosome, resulting in global silencing of the entire region. Because chromosome 2q14.2 is a gene-rich region (eg, containing genes, such as Engrailed, MARCO, SCTR, and INHBB), Clark[10] is trying to determine whether the specific silencing of 1 or more genes in this region is responsible for tumorigenesis.

She compared the expression of these genes, which cover a 4-megabase region, between tumor and normal cells and found that all genes at this locus -- regardless of whether they were specifically methylated or not -- were silenced in tumor cells. This means that not all genes have to be methylated to be silenced. If they lie in a region associated with chromatin alterations, that can be sufficient for their expression to be repressed. Treatment of the cancer cells with 5-azacytidine relieved this suppression, indicating that methylation mediated this silencing. Clark concluded that chromosome 2q14.2 is remodeled by methylation in colorectal cancer cells, and that this is the first example of epigenetic inactivation spanning large chromosomal regions.

Although there is much to learn about the mechanisms by which epigenetic alterations occur in cancer cells and the specific pathways by which these changes lead to tumorigenesis, this field has emerged as an important new area of cancer research. The development of therapeutics that reverse epigenetic alterations in cancer cells, along with prognostic and diagnostic assays based on gene-methylation patterns, are promising new avenues for future improvements in patient care.


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