Researchers uncover genetic signature that predicts colon cancer

Colon cancer may begin when processes that regulate adult stem cells in the colon go awry. A handful of stem cells lie in the bottom of tiny tube-like “crypts” in the epithelium (or lining) of the colon. Stem cells produce daughter cells that proliferate, eventually making their way to the top of the crypt, where they become specialized colon cells. Simply put, mutations in the stem cells lead to mutant daughter cells and cancer.

To try to understand some of these processes, Bruce Boman, M.D., Ph.D., director of the Division of Genetic and Preventive Medicine at Jefferson Medical College of Thomas Jefferson University and at Jefferson’s Kimmel Cancer Center, and his co-workers used a microarray chip to analyze the expression of microRNAs (miRNAs). MiRNAs are tiny pieces of genetic material discovered in recent years that are thought to be important in regulating gene expression and in the development of cancer. The chip carried complementary genetic “probes” for most of the known miRNAs in human and mouse.

The researchers first compared miRNA expression in the bottom tenth of normal colon crypts, which is where stem cells are located, to the other nine-tenths of the crypt, where daughter cells were proliferating. This approach was designed to tell the difference between stem cell and non-stem cell activity.

They also examined miRNA gene expression in colon cancer tissue, finding changes in expression between normal tissue and cancer. More specifically, they found a pattern of 16 miRNA genes that characterizes the crypt bottom. The pattern accurately predicted which colon tissues were normal and which were cancerous.

Dr. Boman, professor of medicine and director of Jefferson’s Hereditary Cancer Center and Gastrointestinal Cancer Program at Jefferson’s Kimmel Cancer Center, presents the team’s findings April 4, 2006 at the annual meeting of the American Association for Cancer Research in Washington, D.C.

“This will not only give us insights into how tissue dynamics are regulated in normal colonic epithelium, but also in the development of cancer as well, where the normal steady state is disrupted,” he says. “It might also help us better understand the stem cell origin of colon cancer.

“If a miRNA is binding to a gene product that is key to differentiation of a cell, and the miRNA is lost, maybe that cell won’t be able to undergo differentiation and will become a cancer cell,” he says. “We’re now looking at the gene targets for the specific miRNAs.

“The exciting part,” notes Dr. Boman, “is that by figuring out which of these molecules are lost in cancer, they can theoretically be replaced. This could have tremendous potential for the development of new drugs.”