Labs find colon cancer gene defect Blood test will screen hereditary disease

August 09, 1991|By Mary Knudson

Scientists at the Johns Hopkins University and in Utah have found a mutated gene responsible for two inherited forms of colon cancer, a discovery expected to lead to screening for the gene in less than a year in people with a family history of colon cancer.

The normal gene performs the function of stopping tumors from developing. But the damaged gene is in effect a fallen soldier no longer capable of defending the colon from an onslaught of benign growths called polyps. These polyps develop by the hundreds, and some of them become cancerous tumors.

"One in 5,000 people have inherited a mutant form of this gene [called APC], and there is a 100 percent probability they will get colon cancer," said Dr. Bert Vogelstein, professor of oncology at the Johns Hopkins Oncology Center.

Colon cancer is the second most common form of cancer in the United States. Some 155,000 cases were diagnosed in 1990, and nearly 61,000 people died from it.

In the majority of colon cancers, the mutated APC gene is not inherited. But this same gene can become mutated from exposure to environmental carcinogens or by chance mutation in the body's continual cell replacement. The APC gene is believed to initiate most cases of colon cancer, Dr. Vogelstein said. Although all those who inherit the defective gene will develop colon cancer, it will afflict only 10 percent to 20 percent of those who develop the mutation after birth.

Curtis Harris, chief of the laboratory of human carcinogenesis at the National Cancer Institute, hailed the discovery as significant for two reasons.

First, a simple blood test will be able to let people know whether they have inherited a mutated form of the gene or not. Half the children of a parent who carries the mutated gene will inherit it.

Second, Dr. Harris said, as a result of the discovery, scientists will now try to develop drugs "that mimic the normal function of this gene."

Developing a drug is a very difficult task and is not expected to happen quickly, but if one is developed, it would provide the first treatment for two very troubling diseases -- familial adenomatous polyposis (FAP) and Gardner's syndrome, a variation of FAP.

People who have inherited the damaged gene develop polyps as teen-agers and during their 20s and get colon cancer by their 30s or 40s, Dr. Vogelstein said. Often they have their entire colon removed.

The screening for this colon cancer gene could be done prenatally as well as after birth.

The announcement of the discovery by the Vogelstein lab appears in the current issue of Science magazine.

The Vogelstein lab shared information with another group of researchers headed by Dr. Raymond White at the University of Utah in Salt Lake City. The Utah group found the same gene and published the results of their research in the current issue of Cell, another scientific journal.

In hunting for the gene, the two teams of researchers looked at damaged genes in families who inherited a colon cancer gene and in tumors of other colon cancer patients and then searched along chromosome 5, where earlier research had indicated the defective gene might be located.

To explain the massive search for the one gene among approximately 100,000, Dr. Vogelstein offered this analogy: If all a human body's genes were unraveled and laid out between Baltimore and Washington, the mutation in one gene would amount to a nick in a table inside one house somewhere between the two cities. But that nick causes major destruction to the gene product, a protein that is key to preventing tumors from forming in the colon, the scientist said.

The majority of colon cancers are caused by a series of assaults from environmental carcinogens on several different genes, beginning with the APC gene. Red meat has been implicated as a cause of colon cancer, for example. Also, genetic errors can occur spontaneously when cells multiply, causing a mutation in a colon gene.

It is possible that in the future a stool test may be devised that could detect the presence of this first gene to become mutated, the APC gene, and such a test would detect the benign tumors before they develop into cancer. When the mutated gene is not inherited but becomes mutated after birth, it does not appear in all cells and therefore would not show up in a blood test, Dr. Vogelstein said.

The Vogelstein lab has been in the forefront of explaining the scientific basis for the development and spread of colon cancer, Dr. Harris said. In earlier research, Dr. Vogelstein has shown that several genes are involved in the progression of colon cancer.

But, until now, "what was missing was the initiating event," Dr. Vogelstein said.

"This [the mutation of the APC gene] is the first event. It is probably involved in the great majority of colon cancer."

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