Genetic Defect That Causes Colon Cancer Is Discovered : Health: Researchers have yet to isolate gene but predict a test to screen entire population within two years.


In a finding that scientists say could save thousands of lives now lost each year to inherited forms of colon cancer, researchers have discovered a genetic defect that produces a strong susceptibility to the disease, the second-deadliest form of cancer in the United States.

The research, to be published Friday in three papers in the journal Science, indicates that virtually every person who carries the defective gene--about one in 200--will develop colon cancer.

“That would certainly make this (gene) one of the most common causes of inherited disease--if not the most common,” said geneticist Albert de la Chapelle of the University of Helsinki, one of the authors of the papers. The new research also indicates, he said, that for the inherited form of colon cancer, genetics is much more important than environmental factors.


The discovery, said molecular biologist Eric Lander of the Massachusetts Institute of Technology, is “the most exciting development in human genetics of the past year”--a year that has already seen the discovery of the genes for Huntington’s disease and Lou Gehrig’s disease.

The researchers have not yet discovered the gene itself, only its approximate location on the human genetic blueprint. But armed with only that information, they predicted that within six months they would have a blood test that could identify members of a family with a history of colon cancer who are likely to develop the disease. And within two years they hope to have identified the gene and developed a test that could be used to screen the entire population for the defect.

“Individuals with the genetic defect could then be more closely monitored for the development of colon cancer so that it can be caught at an earlier stage,” said Dr. Curtis Harris, a clinical oncologist at the National Cancer Institute. “That is particularly important because if colon cancer is caught at an early stage, it is almost always curable.”

Equally important, De la Chapelle said, the test will identify family members who do not have the gene and thus are at low risk of developing colon cancer. Some members of such families now opt for prophylactic removal of the colon, even though they are not sure they will develop the disease. The tests could eliminate some of the unnecessary surgery.

“We have proven beyond any shadow of a doubt that a genetic predisposition for (colon) cancer exists,” and that it is associated with only one gene, said Dr. Bert Vogelstein, a medical geneticist at the Johns Hopkins School of Medicine who, along with De la Chapelle, led the team. “We can now tell who will get (colon cancer) and who will not.”

Colon cancer strikes an estimated 158,000 Americans per year, killing 60,000. It is second only to lung cancer, which kills 143,000 people a year.


Colon cancer is most often detected with tests for blood in the stool and by visual examination of the interior of the colon by endoscopy. Early colon cancer is treated by surgically removing the lesion.

The researchers also found that the defective gene has an unprecedented mechanism of action. When it is activated in an individual cell, perhaps by carcinogens in the diet, it produces a variety of other mutations within that cell, leading to the unrestrained growth that is characteristic of cancer.

The discovery marks the second time that a specific gene has been identified as a cause of colon cancer. Researchers had previously found evidence of a gene that causes an inherited form of colon cancer called familial adenomatous polyposis, or FAP. Patients with FAP develop a thick carpet of polyps on their colons that become cancerous if they are not removed. But FAP accounts for about only 1% of colon cancers.

In contrast, the new defect was found in families with the main form of inherited colon cancer. This inherited form of the disease causes about 15% of all colon cancers--about 24,000 cases a year. But the researchers have also found the defect in many cases of non-inherited forms and believe that the gene causes a significant fraction of those 134,000 cases as well.

Some researchers have long suspected the presence of one or more defective genes in inherited colon cancer. But others have argued that a shared diet or other environmental factors were primarily responsible for causing the disease. The new discovery may finally bring some consensus.

The team found the location of the gene by studying two large families with a history of colon cancer, one in North America and one in New Zealand. After exhaustive studies, they finally determined that the suspect gene was inherited along with a genetic marker on chromosome 2, one of the 23 sets of chromosomes that make up the human genetic blueprint.


The finding means that the actual gene is located very close to the marker. The team is working intensely to isolate the gene. “We are determined to push on very hard,” De la Chapelle said. “We think we could identify it within one or two years.”

Once they found the marker for the gene, researchers discovered something else surprising: a mechanism of tumor formation that had never been seen before. Tumor cells from the patients with the gene were littered with a large number of mutations, many more than are normally found in cancer cells. These mutations, furthermore, differ from patient to patient.

The mutations suggest that the defective colon cancer gene interferes with the replication of DNA--deoxyribonucleic acid, the genetic blueprint of all life--during the normal multiplication of colon cells. Inevitably, these mutations trigger the activity of oncogenes that cause cancer and block the activity of tumor suppressor genes that normally retard cell proliferation.

This new type of cancer initiation, Harris said, could provide a fruitful avenue of research for other forms of the disease as well as opening the door to new therapies.