A Lethal Legacy

By Christine Gorman

For almost a century, medical researchers have tried to figure out why colon cancer seems to run in certain families. Did their misfortune result from blind chance, a shared exposure to some cancer-causing trigger in the environment or their diet? Or could they have inherited a rogue gene that made them more susceptible to malignancy? Now a team led by scientists from Johns Hopkins University and the University of Helsinki believe that they have found the answer. "What has heretofore been called familial colon cancer can now be called heritable colon cancer," says Dr. Bert Vogelstein, professor of oncology at Johns Hopkins. "Our groups have proved beyond any shadow of a doubt that a genetically determined predisposition to colon cancer exists." About 1 in 7 cases of colon cancer -- the second leading cause of cancer deaths in the world -- can be attributed to this faulty gene.

The newly discovered defect does not in itself produce cancer in the way that an inherited defect causes cystic fibrosis or sickle-cell anemia. "What the mutant gene does is create a predisposition to cancer," Vogelstein explains. "And it's only with additional mutations after birth that the cancer will appear."

What is remarkable -- and entirely novel -- about the gene is that it may actively promote the accumulation of genetic errors, eventually causing a cell to become malignant. That was "a major surprise," says Albert de la Chapelle, chairman of the department of medical genetics at the University of Helsinki. "It doesn't work at all like we and others had thought." As reported in Science, the researchers estimate that 1 in 200 people carries the defective gene. Of the 95% of them who will eventually develop cancer, 60% will get colon cancer and the rest will develop a variety of other malignancies, including tumors of the uterus, stomach, pancreas or urinary tract.

In their attempt to locate the renegade gene, the scientists studied two families, one in North America and the other in New Zealand. In both cases, half of all adult family members had developed the disease. By comparing the DNA of the 40-odd family members who had tumors with the DNA of those who did not, the researchers hoped to detect a particular stretch of genes that could be linked to the disease. Such a unique pattern, called a genetic marker, would be a major step toward identifying the specific culprit gene. After discarding 344 potential markers, the scientists finally found one that fit the bill.

Even though the researchers have not yet isolated the gene, they suspect that it represents an entirely new pathway to peril. In the past, most genes linked to cancer, including a few linked to colon cancer, have been genes that play a role in regulating cell division, in some cases stopping cell growth when DNA is damaged. When such genes are themselves deranged, genetic errors can rapidly accumulate. But the newly discovered defect is not in a damage- control gene. Instead, it seems to be a direct agent of damage that somehow unleashes wave upon wave of DNA mutations over the course of a lifetime. As a result, a single inherited trait leads to "tens of thousands of alterations throughout the genome," Vogelstein marvels.

This fundamental instability may help explain why patients suffering from hereditary colon cancer seem to respond better to treatment than those whose disease arises in other ways. Apparently their tumor cells are already so heavily damaged that the malignant tissue is actually more susceptible to chemotherapy and radiation than other types of cancer cells.

Just as important, the marker may lead to better screening tests. Early detection makes all the difference to colon-cancer patients. About 90% of people whose tumors are found early are still alive five years after their diagnosis. That figure plummets to less than 10% once the cancer has spread beyond the intestines. However, according to a recent study, the most widely used screening test, which detects blood in stool samples, misses more than 70% of all tumors.

Vogelstein expects that within three years there will be a better diagnostic test based on the newly discovered genetic defect. The first to benefit from such a blood test will be the 5 million to 10 million Americans who are now considered to be at an increased risk of colon cancer because of a strong family history (usually defined as having three or more relatives with the disease, one of them stricken before age 50). The test could cost $300 a family, according to Vogelstein. About three-fourths of family members will learn that they do not carry the gene. That does not means that they are immune to colon cancer, just that they bear an average risk (a 1-in-20 chance during their lifetime). The other 25% will probably undergo a colonoscopy, in which a fiber-optic scope is used to search for growths in the colon. The $1,000 procedure would then become an annual routine.

Eventually, even people who have no family history of colon cancer could benefit from the current findings. Once all the genes whose damage can lead to intestinal tumors have been discovered, researchers may be able to detect such dangerous changes whenever they occur. "DNA testing as we know it now is not cost efficient," says Dr. Funmi Olopade, professor of oncology at the University of Chicago. "But the way technology is moving, 10 years from now this will no longer be such an exorbitant test to perform."

With reporting by J. Madeleine Nash/Chicago and Dick Thompson/Washington