Researchers discover why mutant gene causes colon cancer

Discovery common to zebrafish and humans may lead to therapies that interrupt colon cancer development

Mutations in the adenomatous polyposis coli (APC) tumor suppressor gene have been found to cause 85 percent of colon cancers. Now researchers at the University of Utah’s Huntsman Cancer Institute know why. In a paper published on-line Sept. 9 in the Journal of Biological Chemistry, they explain that APC controls the conversion of dietary vitamin A into retinoic acid. If this process is impaired, colon cancer can result.

“For a long time, scientists believed they knew what the APC gene did – that it regulated cell growth and division – but now we know we’ve been missing a big piece of the picture,” reports David Jones, Ph.D., principal investigator of the study and leader of HCI’s Colon Cancer Scientific Program. “What we didn’t know was that it converts vitamin A into retinoic acid, which is vital for normal colon cell development.”

Jones’ lab had recently demonstrated that lack of retinoic acid, induced by mutating the APC gene, led to cancerous tumors in human colon cell lines. The new study blocked APC function in zebrafish and demonstrated that when the APC gene was blocked, the fish embryos lacked normal intestinal lining cells. When the embryos were treated with retinoic acid, normal cell development was restored. Because zebrafish and humans share many genes, including the APC gene, researchers often use the little black-and-white striped fish as models to study various aspects of human development.

“Implications of this study are far reaching,” Jones says. “We have long suspected that vitamin A was helpful in preventing certain cancers, including colon cancer. With this new understanding, it may be possible to bypass a non-functioning APC gene by introducing retinoids as a form of chemoprevention, and thus control the undifferentiated and uncontrolled growth of colon cells that results in colon cancer.”

Several years ago, University of Utah researchers identified the APC gene, as well as an inherited colon cancer predisposition known as familial adenomatous polyposis (FAP) that occurs in people who have APC mutations. In this inherited syndrome, hundreds to thousands of pre-cancerous growths called adenomatous polyps form in the colon, usually beginning before a person is 16 years old. The lifetime risk for people with this inherited mutation is 100 percent. Scientists have since determined that an acquired mutation of the APC gene is also found in 85 percent of sporadic colon cancer. Colon cancer is the number two cancer killer in the United States.