British researchers have identified a gene whose absence may be a principal cause of a quarter or more of all colon cancers, according to a report published yesterday.
The researchers said that both a rare, inherited form of colon cancer and the common variety of the disease may be caused by the absence of the gene, whose location on the human chromosome they identified.
In 25 percent to 40 percent of the colon tumors studied, a gene was found missing or damaged on the patch of genetic material called chromosome five, the researchers said. They also found that people who have inherited a strong predisposition to the rarer colon cancer also show a missing gene on chromosome five.
Dr. Walter F. Bodmer, leader of the team at the Imperial Cancer Research Fund in London, speculated that the missing gene is likely to be one that prevents cancer in the colon by keeping the cells from making growth chemicals. The main characteristic of tumor cells is that they grow when and where they should not, ignoring cellular signals to halt.
It is the first time a gene region has been located in any of the major cancers, and is among the first of a whole new class of genes being found whose loss, rather than presence, is the trigger of cancer.
"This gives us a new insight into the basic mechanism underlying colon cancer, one of the most deadly and widespread cancers," said Dr. Jeffrey Sklar, a Stanford University pathologist.
Colon cancer is the most common of all the major cancers and the second most deadly, after lung cancer. About 145,000 people will get colon cancer this year in the United States, and 60,000 people will die from the disease, the American Cancer Society estimates.
The find, reported in the Aug. 12 issue of the British journal Nature, may allow researchers to identify at birth those people who are genetically predisposed to get colon cancer. About one in 5,000 to 10,000 have this condition, called familial adenomatous polyposis (FAP).
The discovery of the region where the gene is located should lead to pinpointing the location of the gene itself within a couple of years, Bodmer said, allowing early diagnosis for those with common colon cancer. Finding the gene itself would also be a critical event for researchers, who could then directly manipulate the gene in the laboratory to see how it prevents cancer.
Treatments developed from this research may be years in the future.
The development is one of a growing string of insights into the genetic basis of cancer. Genetic defects were not thought to cause cancer until recent years. But now researchers have been able to link specific genes to specific cancers, and sort out two kinds of genetic action that can cause cancer -- a positive and a negative one.
Cancer may be triggered by the action of growth-promoting genes called cancer genes or "oncogenes," or the failure to act of growth-suppressing gene called anticancer genes or "anti-oncogenes."
The genes are the long strands of molecules present in identical copies in all the cells of all living creatures. They represent the programs that govern daily activity as well as store all the information passed from parent to child.
There are many genes on each chromosome and 23 pairs of chromosomes that constitute the human genetic store.
Because the whole set of genes on the chromosomes are billions of molecules long, and every cell has a full set, it is extremely difficult to determine the location and action of any one gene. Techniques of genetic engineering have allowed researchers in the past decade to use chemical "markers" to distinguish between a normal set of genes and one with a genes added, missing or grossly altered.
Using this method, the British team studied families with FAP. The disease appears in childhood, and its chief symptom is the growth of hundreds or thousands of small polyps, "like a carpet in the intestine," as one researcher put it. Over time, some of these growths will develop into the tumors of colon cancer.
The researchers located a marker that is apparently very near the site of the missing gene, Bodmer said.
The team also reported examining 45 colon tumors and deciphering a similar pattern of missing genes in at least 23 percent and posssibly as many 40 percent of them. Technical difficulties prevented a completely accurate count, he said.
Dr. Alfred Knudson, a medical geneticist at the Institute for Cancer Research at the Fox Chase Cancer Center in Philadelphia, is the researcher who first put forward the "lost gene" scenario for colon cancer.
One likely scenario for the development of the disease which arises out of the Knudson model and the British team's work is that people who have inherited FAP are born with one chromosome five without the protective gene, and one with the gene intact.
Thus, perhaps half the protective chemical action of the gene is lost and polyps readily form. Another step, the loss of the gene on the second chromosome five, is still necessary to cause the polyps to become cancerous.
Because diet is also believed to be a major contributing factor to the disease, it seems likely that the way the genes are lost or damaged comes through eating certain foods. These may contain chemicals or bacteria that produce toxic chemicals that damage the intestinal cells and genes, while the food is being digested.
A high-fiber diet is believed to lower the risk of colon cancer because it causes rapid elimination, cutting short the time food may remain to damage the intestine.
In the noninherited form of colon cancer, the common form of the disease, both genes are damaged by environmental factors rather than having one absent at birth. Thus, the cancer is commonly found in older people whose intestines have had long exposure to potentially damaging foods.