Gene That Causes Inherited Colon Cancers Discovered
Two teams of researchers have independently discovered the defective gene that causes the majority of inherited colon cancers, a finding that should make it possible to screen for susceptibility to the disease not only in families with a history of the disorder, but in the population at large.
The gene is carried by one in 200 people. Virtually all will develop colon cancer, making the gene one of the most common causes of inherited disease. A screening test would be quite valuable because colon cancer is curable if detected early.
Researchers said a blood test for the gene could be available in as little as six months, and that it would probably cost about $1,000, about the same as the colonoscopy that is used to search for colon tumors. They predicted that the price would decrease substantially over time.
“It seems likely that this will be the first (genetic) test that will find its way into general clinical practice, and it will usher in a new era of genetic medicine,” said Dr. Francis Collins, director of the National Center for Human Genome Research.
Colon cancer strikes 158,000 Americans each year, killing 60,000. Although the inherited form accounts for only 15% of those cancers, preliminary evidence suggests that sporadic mutations of the gene cause a large fraction of non-familial cases--as well as many other types of the disease, including stomach, ovarian and uterine cancer.
The healthy gene, the researchers report today and Dec. 17 in the journal Cell, serves as a kind of editor to prevent the accumulation of mutations in genetic material when cells replicate, like a computer program that protects against the intrusion of a computer virus.
When the gene malfunctions, the genetic information becomes garbled, touching off a cascade of events that leads to the formation of a tumor.
“The identification of this gene and its mutations may be a turning point in the quest for more accurate prediction of risk and prevention of several cancer forms,” said Dr. Albert de la Chapelle of the University of Helsinki.
The screening test should initially be used on anyone with a close relative who has suffered from either colon cancer or uterine cancer, the researchers said. “That’s millions and millions of people,” Dr. Bert Vogelstein of Johns Hopkins University, one of the discoverers, said at a news conference Wednesday.
Those who do not have the gene would be freed from anxiety and expensive tests, while those who do would be encouraged to adopt a more healthful lifestyle and have more frequent examinations, increasing the likelihood of early detection.
As the price decreases, the screening could be expanded among the general population.
Although genetic tests are widely used in families with a history of inherited disorders, such as Huntington’s disease, amyotrophic lateral sclerosis and a host of others, the number of people tested for each disease is small compared to those who could be tested for the colon cancer gene, genome research project director Collins said.
“This kind of success is what we had in mind when we started the genome project,” a $3-billion, 15-year attempt to identify each of the estimated 100,000 genes that comprise the human genome, the complete blueprint for a human, Collins said.
Researchers have previously identified a large number of other genes, called oncogenes, that play a role in the initiation of cancer when they are defective. Vogelstein, one of the predominant researchers studying colon cancer, has shown that it generally requires the cooperative action of half a dozen or more oncogenes to produce a tumor.
But the newly identified gene, MSH2, is qualitatively different from the others. In effect, MSH2 creates other oncogenes by allowing random mutations to accumulate in cells. Eventually, those mutations activate enough oncogenes for a tumor to form. The presence of MSH2 is thus far more devastating than that of any other oncogene, said geneticist Richard Kolodner of the Dana-Farber Cancer Institute in Boston, a co-leader of the second team.
Furthermore, “we know exactly what this gene does, which is not the case with many of the cancer genes of the past,” Kolodner said. “That’s the true importance of this discovery.”
Researchers know how the gene works because Kolodner and microbiologist Richard Fishel of the University of Vermont have studied a virtually identical gene in bacteria and yeast for nearly 20 years. They turned their attention to humans six months ago when Vogelstein and Chapelle announced that they had narrowed the search for the colon cancer gene to a small region on chromosome 2, one of the 23 pairs of chromosomes in the human genome.
The finish of the race for the gene proved very close. Kolodner and Fishel barely nosed out the other team. Their paper is published today in Cell. Vogelstein and his colleagues’ paper will appear in the same journal in two weeks.
The discovery could lead to new therapies as well as gene screening, Kolodner said.
