A multinational team of researchers has discovered a gene that plays a key role in the development of colon cancer, opening the way for tests to identify high-risk individuals and for early detection of the disease.
The discovery, reported today in the journal Science, may also lead to the development of new therapies for colon cancer, which is the second most common form of cancer in the United States. Last year, it struck 155,000 people and killed 61,000.
"That's a long-sought gene because it seems to play a role in (two different types of colon cancer)," said oncologist J. Michael Bishop of UC San Francisco. "If they've got it, that's quite important."
"This is a very significant finding," added molecular biologist Robert Weinberg of the Massachusetts Institute of Technology. "This could represent the first entree we have into understanding why many families have high rates of colon carcinoma."
The discovery is the most recent development in the explosive growth of the field of cancer genetics. To date, researchers have identified at least five dozen genes that are linked to the onset of malignancy in humans.
But the tentatively identified gene--which is also involved in the development of colon polyps--is one of the most exciting so far, experts said, because colon cancer is so widespread and because the gene plays such a key role in the onset of the disease. Many believe that developing the ability to overcome the effects of the new gene, called MCC (for Mutated in Colon Cancer), could halt colon cancer in its tracks.
The team found MCC on the so-called long arm of chromosome 5, one of the 46 chromosomes that carry the genetic blueprint of a human.
Much research over the last decade had shown that a defect in a specific region of chromosome 5 is found in at least 50% of colon tumors. MCC, the researchers report today, is most likely the single gene within that region that suffers the damage.
Bert Vogelstein of Johns Hopkins University, one of the lead authors on today's report and his colleagues believe MCC causes the inherited disease \o7 familial adenomatous polyposis\f7 , commonly called FAP. Members of FAP families are born with a genetic defect in MCC that produces large numbers of benign polyps, or growths, in their colons.
These polyps often become tumors, although FAP is believed to account for only a small fraction of colon cancers, perhaps 1%. But previous research had suggested that damage to the same gene occurs in the bulk of those colon cancers that seemingly strike the population at random.
Vogelstein and his colleagues had previously identified three other genes that are associated with colon cancer. They now believe that all four must be damaged for malignancy to develop, and that the damage follows a precise pattern.
Damage to one gene, most likely MCC, they believe, gives rise to a benign polyp. Damage to a second gene causes the polyp to expand in size and become more irregular in shape. Changes in the third gene in at least one of the polyp cells causes the benign tumor to become malignant. And finally, mutations in the fourth cause cells in the tumor to metastasize--break off and invade other sites in the body.
"By having all the pieces of the puzzle at our disposal, we can begin to put together how these genes are interacting with each other . . . and try to turn on and turn off cancer," said molecular biologist Carl Barrett of the National Institute of Environmental Health Sciences in Research Triangle Park, N.C.
MCC's position at the beginning of this cascade makes it a particularly appropriate target for such attempts, researchers agree. One way to do that would be by gene therapy, replacing the defective MCC with a healthy form of the gene. So far, however, researchers have been able to successfully introduce new genes only into isolated cells, not into cells inside an animal's body.
In the short term, therefore, scientists think they might be more successful by designing drugs that would replace the cellular function lost when MCC is defective. Although the researchers have not identified the precise function of MCC yet, its structure suggests that it is the blueprint for a protein that carries growth signals within a cell. Researchers may be able to find a simple chemical that can do the same thing.
Vogelstein has also predicted that it might be possible to find cells in the urine containing one or more of the genetic defects. Screening for such cells might reveal the presence of a tumor much earlier than tests now in use.