Genetic clues to colorectal tumors.

Imagine a truck rumbling downhill with a stuck accelerator. The truck flies off the cliff. This time a diagnosis of the problem would focus on the accelerator, not the brakes.

Whereas the RB gene speeds cancer's progress when shut off, the ras gene causes trouble when a mutation turns it on. Like a racing accelerator, the activated ras gene tells the cell to keep on truckin'.

Scientists believe a mutation in this gene is involved in the very early stages of colon and rectal cancer, which will kill an estimated 58,300 people in the United States this year, according to the American Cancer Society. If diagnosed early, most people with colorectal cancer can expect to live at least five years. However, the disease can remain hidden, producing only mild symptoms such as a change in bowel habits.

Doctors searching for signs of this potentially lethal disease must rely on a test that detects blood in stool samples. The stool test is an inexact method that can miss some colorectal cancers while flagging certain noncancerous conditions such as hemorrhoids.

Now, researchers have developed a test that detects mutations in the ras gene and may one day help identify healthy people at risk of developing colorectal cancer.

In the April 3 SCIENCE, David Sidransky of Johns Hopkins University in Baltimore and his colleagues describe a stool test that detects mutations in the ras gene.

In theory, the notion of looking for the wayward gene sounds simple enough. In practice, however, the process is a little like looking for the proverbial needle in a haystack.

Stool is a mixture of undigested food, mucus and by-products of the digestive process. "We were trying to isolate cells that had sloughed off the human colon, which are only a small percentage of that mess," Sidransky says. The investigators had to find not just healthy colon cells but also cells from the tumor itself, a task that required a powerful molecular probe. The team turned to polymerase chain reaction (PCR), a technique that can identify trace amounts of genetic material.

To begin their experiment, they focused on 24 men and women who had either a malignant tumor or a polyp, a wart-like growth. Using PCR to analyze tumor tissue and polyps, the researchers found that nine of the 24 people had a mutation in the ras gene.

Then came the crucial part of the experiment. The scientists used PCR to test stool samples from the nine people with known mutations. They found that PCR identified the problem ras gene in eight of the nine cases, including two people who had only benign polyps.

The Hopkins scientists believe their method may one day provide physicians with a reliable way of screening stool samples for the earliest signs of colon and rectal trouble, perhaps even before a benign tumor or polyp turns malignant. If oncologists can find very tiny tumors, the chances of curing a patient with surgery are much better, Sidransky says.

For now, however, the technique remains experimental. Further testing with larger groups of people is needed to determine whether such an approach can accurately detect tiny tumors and polyps likely to become malignant. This particular method looks for mutations in the ras gene, which appears in less than 50 percent of all colorectal cancers.

What about people who lack this mutation? The team hopes to develop a screening method that would also spot other common genetic mutations that can lead to colon or rectal cancer. Sidransky believes such a test will reach the market in about five years.