2nd Colon Cancer Gene Found; Tests Expected Soon
With the discovery of a second colon cancer gene, researchers reported Wednesday that they now have identified the causes of more than 90% of the inherited form of the disease.
Between them, the two genes are responsible for one in every six of the 156,000 new cases of colon cancer diagnosed each year. They also appear to account for as many as 30% of sporadic (non-inherited) cases of colon cancer.
Researchers expect within a few months to develop diagnostic tests that will show whether an individual has either gene. If one of the genes is present, doctors can monitor for tumors frequently, enabling their detection while they are still curable by surgery.
“We can reduce cancer deaths in these families by over 90%,” said Dr. Bert Vogelstein of Johns Hopkins University, a co-leader of one of the two groups that report the discovery today in the British journal Nature and Friday in Science.
The discovery could also lead to new anti-cancer drugs within three to five years, predicted microbiologist Richard Fishel of the University of Vermont, a leader of the other team, which reported its findings in Nature. “I am very confident that in short order we will be able to develop appropriate therapeutics based on our knowledge of these genes,” he said.
The same two teams reported the discovery of the first colon cancer gene in December.
Both genes, which are found on different chromosomes, act like the spell-check function in a word processing program, checking newly synthesized DNA to ensure that no mistakes--mutations--occur during cellular proliferation. When either gene is defective, “you accumulate these alterations at an extremely high rate and cancer is the result,” said Fishel. Inherited colon cancer usually strikes before the age of 50.
“This is a great triumph for science,” said Department of Health and Human Services Secretary Donna Shalala. “These discoveries . . . will lead to screening tests for high-risk individuals soon. Doctors will be able to save countless lives and prevent much needless suffering.”
Shalala also raised the concern, shared by the researchers, that screening for the genes could sharply impair the ability of carriers--people who have the genes--to purchase health insurance. Because virtually everyone who has the genes will develop cancer, carriers might be excluded from coverage. About one in every 200 people has one of the defective genes, Vogelstein said, making it the most common genetic defect in the world.
Both groups said they have tentatively identified a third gene that accounts for most of the remaining 5% to 10% of inherited colon cancer, formally called hereditary nonpolyposis colon cancer. In 1991, other scientists announced the discovery of a gene that causes a rarer form of inherited colon cancer, called familial adenomatous polyposis, that accounts for perhaps 1% of all cases of colon cancer.
Researchers know a great deal about how the two genes work because Fishel and colleague Richard Kolodner, a geneticist at the Dana-Farber Cancer Institute in Boston, have studied virtually identical genes in bacteria and yeast for nearly 20 years. In bacteria, the genes produce two proteins that carry out the “spell-check” function.
The first protein scans newly synthesized DNA to check for any errors that have occurred during its synthesis. If an error is found, the second protein binds to the first and repairs the error.
If the first gene is defective, mistakes in DNA formation are not recognized. If the second gene is defective, mistakes are not repaired. Either way, mistakes accumulate until a cancer cell is formed.
The researchers are confident an identical process occurs with the human genes, but that has not been proved.
The quick discovery of the human genes, Fishel said in an interview, came about because of the extensive knowledge that had already been compiled about the bacterial genes, a classic example of basic research as opposed to applied. “This discovery is a coup for the basic research process in the United States,” noted Dr. George Vande Woude of the National Cancer Institute.
Both groups are actively developing laboratory tests that could be used to screen members of affected families. That process is complicated, Fishel said, because at least a dozen different mutations of the new gene have been identified and each has to be taken into account in any potential screen.
The test is expected to initially cost about $1,000, about the same as the colonoscopy now used to search for colon tumors. Such testing will be most appropriate in families where at least three members have been diagnosed with colon or rectal tumors within two generations. Fishel said the testing should be conducted “as early as possible,” preferably shortly after birth, because the cancer can strike in the teens. Carriers can also adjust their lifestyle--adopting a diet low in fat and high in fiber, for example--to reduce risks.
The cost of the screening is expected to decline with increased use, eventually permitting the test to be applied to the whole population.
There is some evidence that the genes may play a role in other cancers as well, including those of the lungs, intestine, uterus and ovaries. Such tumors occur at a high rate in families with a history of colon cancer, and defective versions of the genes have been identified in some of these tumors from individuals. Gene carriers would also be monitored for the development of these types of tumors.
