Joe Maciag

What if I told you there may be a new way of determining whether non-cancerous cells have the potential to form malignancies. If this were possible, it may lead to earlier diagnosis and treatment. The method may sound like a way to see into the future, but it is not fictitious.

Over the last decade scientists have uncovered new evidence in the field of DNA methylation due to advances in technology. DNA methylation is the covalent addition of a methyl group (CH₃) at position 5 of the nucleotide base cytosine (see picture below).

The proteins responsible for the addition of these methyl groups are known as DNMTs (DNA methyl transferases). Humans contain genes that encode for five DNMTs, but only three appear to be directly involved in the addition of methyl groups to cytosine. One of the many reasons that DNA methylation is so harmful is because it has the potential to silence gene expression. The modification is thought to be irreversible, although there was speculation in the late 1990s that there may be a DNA demethylase that can reverse this addition. To date, no enzyme has been found, but the search is still on.

Epigenetic Markers

Scientists have observed that these additions to our DNA have “silenced” certain genes, which in turn cause low production of necessary miRNA or of proteins that are tumor suppressors. When a pattern of hypermethylation (increased methylation) occurs, transcription factors are not able to bind and subsequently transcribe the gene.

With emerging technologies in epigenetic mapping, researchers are able to locate each of the (CH₃) methyl groups on cytosine. The modifications are more prevalent in regions of the DNA known as CpG islands, which are so named because of their high density of both cytosine and guanine. In addition, around 60% of human promoters are present in these CpG islands.

Methylation of promoters as well as the upstream regions associated with said promoters has been shown to repress transcription. Malignant tumors can arise from the down regulated genes just as easily as it can from over expression of genes. For example, when tumor suppressor genes coding for proteins such as p53 are not transcribed, cells are allowed to proliferate without recourse, leading to cancerous tumors.

Using this information, scientists have located many genes in precancerous cells that tend to be methylated during metastasis. These genes are known as being cancer-specific and can be used as a biomarker for cancer. Many of the genes have been shown to be hypermethylated in multiple cancer types, but some are specific to one type of cancer.

Examples of cancer-related genes (Kulis, 2010)

You may ask yourself, why do we need another tool in order to verify whether a tumor is malignant or benign? Doctors already possess many ways of distinguishing tumorigenic vs. non–tumorigenic cells, don’t they? While it’s true that they do have the ability to separate the two, some of the procedures they use come at a cost. Some procedures are very invasive, causing patients discomfort, and some are not as reliable as one would like.

In addition, hypermethylation biomarkers can provide insight into what a tumor may transform into. Just because a tumor starts out benign does not mean that it will stay that way. This approach is like a crystal ball for scientists: methylation patterns can show whether or not a lesion can turn into cancer.

Gene methylation and cancer: Tubular adenoma and Villous adenoma are benign tumors that can become malignant if not treated. These tumors possess elevated levels of methylation in their promoter regions.

The field is in its infancy, and researchers have only begun to unravel the full story that DNA methylation has to tell us. These epigenetic markers are potential targets in the reversal of metastasis or even a preemptive measure to stop a tumor before it begins to grow.

References:
Kobayashi, Y., Absher, D., Gulzar, Z., Young, S., McKenney, J., Peehl, D., Brooks, J., Myers, R., & Sherlock, G. (2011). DNA methylation profiling reveals novel biomarkers and important roles for DNA methyltransferases in prostate cancer Genome Research, 21 (7), 1017-1027 DOI: 10.1101/gr.119487.110

Yi, J., Dhir, M., Guzzetta, A., Iacobuzio-Donahue, C., Heo, K., Yang, K., Suzuki, H., Toyota, M., Kim, H., & Ahuja, N. (2012). DNA methylation biomarker candidates for early detection of colon cancer Tumor Biology, 33 (2), 363-372 DOI: 10.1007/s13277-011-0302-2

Marta Kulis, Manel Esteller (2010). DNA methylation and cancer Advances in Genetics, 70, 27-56 DOI: 10.1016/B978-0-12-380866-0.60002-2