A research team at the Karolinska Institute and the University of Helsinki has demonstrated that the switches that regulate gene expression play a critical role in the development of cancer. Writing in Science, the investigators looked at a gene region that contains a single nucleotide variant (rs6983267) associated with increased risk for cancer. They reported that, by removing this region, tumor formation was greatly reduced.
Working with mice, the scientists analyzed rs6983267 in a region associated with a higher risk for developing colorectal and prostate cancers, but whose mechanism of action has been unclear. Although this variant increases cancer risk only by 20%, it is very common and therefore accounts for more inherited cancer than any other currently known genetic variant or mutation, according to Jussi Taipale, Ph.D., the Karolinska researcher who led the study.
The scientists removed the gene region containing the risk variant from the mouse genome, and found that as a result the mice were healthy but displayed a small decrease in the expression of a nearby cancer gene (MYC). However, when these mice were tested for the ability to form tumors after activation of an oncogenic signal that causes colorectal cancer in humans, they showed strong resistance to tumor formation. The removed gene region thus appears to act as an important gene switch promoting cancer, and without it tumors develop much more rarely.
According to the scientists, these results show that, although the gene variants in general have a small impact on disease development, the gene switches in which they reside can play a major role.
“Our study also highlights that growth of normal cells and cancer cells is driven by different gene switches, suggesting that further work to find ways to control the activity of such disease-specific switches could lead to novel, highly specific approaches for therapeutic intervention,” noted Dr. Taipale.
Separately, Yale researchers reported in Cancer Research that they, too, had manipulated a genetic switch to halt the growth of cancer in mice and to prevent tumors from forming. The activation of a single microRNA (miRNA-34) managed to neutralize the effects of K-ras and p53 in a mouse model of lung carcinoma.
“This is pretty much the best preclinical data that show microRNAs can be effective in lung cancer treatment,” said Frank Slack, Ph.D., professor of molecular, cellular & developmental biology, researcher for the Yale Cancer Center, and senior author of the paper. “These cancer genes are identical to ones found in many forms of human cancers and we are hopeful the microRNA will be of therapeutic benefit in human cancer.”