The study, led by researchers at the Ohio State University Comprehensive Cancer Center, shows that the inherited mutation greatly reduces the gene’s protective activity. Furthermore, a second kind of change occurs later that turns the gene off altogether, leading to leukemia. This latter alteration is a chemical change that is not inherited.
The mutation was found in a gene called DAPK1, which normally helps trigger the death of cells before they become cancerous. Researchers identified the mutation by testing a family in which the father, four sons, a grandson and a distant female relative developed this form of leukemia.
The chemical change is called DNA methylation. Healthy cells use this process to silence unneeded genes. But abnormal DNA methylation can turn off genes that control cell growth, and that lead to tumor growth. The findings provide evidence that some genes might contribute to cancer even when they are not silenced entirely.
“This inherited change is remarkably subtle,” says co-principal investigator Albert de la Chapelle, professor of molecular virology, immunology and medical genetics and a researcher with the Ohio State human cancer genetics program. “It does not shut down the gene, but just lowers its expression somewhat.
“Recently, many cancer geneticists have come to believe that such subtle changes are common causes of cancer, and this is one of the first, strong examples of that principle.”