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Tracking a Colon-Cancer Gene |
By 1990, researchers had the techniques that they needed to search for the gene that causes an important form of colon cancer known as hereditary nonpolyposis colorectal cancer (HNPCC). People who inherit the HNPCC gene have an 80% or greater chance of developing colon cancer and other cancers, usually at an early age. Women with the gene also face a markedly increased risk of uterine and ovarian cancer.
The search for the HNPCC gene had actually begun more than 30 years earlier in the laboratories of several scientists who were working on bacteria and yeast to learn what happens to the occasional genetic errors that occur during sexual reproduction or when DNA is damaged by particular chemicals. These errors stem from DNA that has incorrectly paired bases (an A paired with a G, for example, instead of with a T). Studies showed that bacterial and yeast cells had a way of snipping out the mismatched bases in a process called mismatch repair. Through genetic analysis in both bacteria and yeast, several genes critical to the mismatch pathway were identified and their protein products were characterized.
Paul Modrich had devoted much of his academic career to working out the details of this repair mechanism in bacteria. By 1992, Richard Kolodner and his colleagues at the Dana Farber Cancer Institute in Boston had isolated a gene called Mut S homolog 2 (MSH2), which was needed for mismatch repair in yeast. Kolodner speculated that people probably also had a similar gene that governed mismatch repair. Because the process is vital to the functioning of cells, Kolodner assumed that errors in a human version of MSH2 and other mismatch-repair genes would cause some human diseases. With that in mind, he and his collaborators used PCR to detect the human MSH2 gene at the end of 1993.
Meanwhile, Bert Vogelstein at Johns Hopkins University and his colleagues in Finland were studying the families of people afflicted with HNPCC. They had used positional cloning to pinpoint the gene for the condition and published its sequence two weeks after Kolodner and his collaborators had published the sequence of their human MSH2 gene. The two sequences were identical: Vogelstein's disease gene for HNPCC was the same as Kolodner's MSH2 gene. Shortly after, a second mismatch-repair gene was found also to cause HNPCC. Vogelstein, Kolodner, and other researchers have since developed genetic tests for these two genes. The tests can tell people, in families prone to HNPCC, whether they have one of the genes that foster it. As many as 1 in 200, or 1.25 million Americans, may carry one or the other of these altered genes. People found to carry an altered gene can be counseled to adopt a high-fiber, low-fat diet in the hope of preventing cancer. They can also be advised to start yearly colon examinations at about age 30. Such examinations should help physicians to detect any precancerous growths on the colon so that they can remove them before the growths turn malignant. For those people, like Beth, who turn out not to carry the altered genes, the diagnostic test can provide a huge relief, removing the fear they have lived under as well as the need for frequent colon examinations.
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