Mutations Not The Only Gene Defect That Leads To Cancer

Another kind of defect, one that turns off genes without changing their DNA, is also at work, and probably to a much greater degree than ever suspected.

The findings, published recently in the journal Nature Genetics, strongly suggest that an unknown number of genes - over and above those affected by mutations - are involved in the cancer process.

"Science has been studying changes and alterations at the genetic level in cancer cells, and we thought we understood tumor progression," said Christoph Plass, assistant professor of molecular virology, immunology, and molecular genetics at the Ohio State University Comprehensive Cancer Center.

"Now there is this second layer of complexity. A lot ofscientists are going to be kept very busy trying to understand this," said Plass, coordinator and one of the principal investigators of the study.

This type of gene defect involves a process known as DNA methylation. Normally, healthy cells use DNA methylation during development and throughout life to turn off genes that are not needed. In cancer cells, aberrant DNA methylation turns off genes that would normally prevent inappropriate cell division. In other words, it shuts down one of the body's best mechanisms that prevents a cell from becoming cancerous.

"This is the first time in which DNA methylation has been studied in human cancer on a scale this large and in which different tumor types have been compared."

The research presented several surprises.

"When we began this study, we expected to find methylation in a few key tumor suppressor genes," he said. "Nobody expected to find this high degree of methylation."

In fact, the researchers found that up to 10 percent of the genes in some tumors types were inactivated by methylation.

"This was surprising because it suggests that 4,000 to 5,000 genes might be deregulated (turned off) by aberrant DNA methylation in some types of tumors."

There were other surprises as well.

DNA methylation in cancer was discovered about 10 years ago and until now, people believed that its role in cancer was limited to inactivating tumor-suppressor genes.

"We were surprised to find that only 40 percent of the methylation events we detected involved changes in gene activation, while the other 60 percent did not," said Plass. "The genes represented by this 40 percent should be investigated for their relationship to cancer.

"The function of those genes whose activation remains unchanged by methylation is unclear, though, as are the consequences of this methylation for the cell. We believe that methylation may contribute to the overall genetic instability in the tumor." Genetic instability refers to the ease with which malignant cells can develop additional mutations.

The researchers also found that the pattern of methylation was very specific for some types of tumors.

"This aberrant methylation doesn't occur at random," he said. "In some tumor types - leukemia and head and neck cancer, for example - certain genes are methylated in very specific places, and we can use those sites as markers for certain tumor types."

Aberrant DNA methylation may therefore provide a way to identify subtypes of cancer that respond better to certain kinds of treatment.

Plass said there is also preliminary evidence suggesting that resistance to chemotherapy is in some cases linked to the degree of aberrant methylation in some tumors.

The study, conducted by Plass and a large team of researchers, examined 98 tumor samples to determine if any of the islands were methylated. The samples came from seven types of tumors: breast, colon, glioma, head and neck, leukemia, testicular, and primitive neuroectodermal tumors of childhood (PNET).

How DNA methylation turns off genes, and why it goes wrong in cancer cells is still unknown.