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Gene discovery: key to colon cancer test.

Two international research teams, working independently, have isolated the gene that, when defective, causes cells of the large intestine to form polyps that may become cancerous. The discovery is expected to lead to a more definitive test for an inherited predisposition to precancerous colon polyps. It should also improve scientists' understanding of all forms of colorectal cancer, the researchers say, and may one day enable physicians to use a genetic strategy to battle the disease.

The two teams located the gene underlying familial adenomatous polyposis (FAP), an inherited disorder affecting 1 in 5,000 people in the United States. The researchers named the gene APC, for adenomatous polyposis coli. Beginning in their late teens or twenties, people who have inherited a defective copy of this gene from one or both parents develop hundreds or thousands of tissue blebs, or polyps, in the colon. Because their colon polyps are very likely to develop into cancer, most members of FAP-prone families undergo annual colon examinations, and many of those with large numbers of polyps have the colon surgically removed.

The researchers report the discovery of the APC gene in four papers: two in the Aug. 9 Science and two in the Aug. 9 Cell. Both groups concentrated their searches on a small region of chromosome 5 called the q21 band, which is missing in some people with FAP.

One group pinned down the APC gene by finding many of the genes from band q21 that are "turned on" in normal colon cells, and then determining which of those genes were damaged in patients with FAP and in patients with colorectal cancer but not FAP. The team, led by Bert Vogelstein and Kenneth W. Kinzler of the Johns Hopkins University School of Medicine in Baltimore and by Yusuke Nakamura of the Tokyo Cancer Institute, describes its work in Science.

The other group, whose results appear in Cell, took the opposite approach. The U.S. and French investigators, led by Ray White at the University of Utah Health Sciences Center in Salt Lake City, found the APC gene by searching for common mutations in the chromosome 5 q21 band of two FAP patients. To confirm that the gene shared by the two patients indeed underlies FAP, they identified APC mutations in four additional, unrelated patients with FAP.

Both teams speculate that a defect in the gene serves as the first half of the one-two punch that results in colorectal cancer. Under this scenario, cancer-prone polyps develop in people who inherit a defective APC gene and in people whose normal APC gene suffers environmentally inflicted damage. Whatever its source, the APC defect primes these individuals for a second genetic error - possibly involving the oncogenes p53 or ras (SN: 9/17/88, p.187) - that converts their polyps to cancer.

"We think a mutation in the APC gene is one of the early changes that take place in all colon cancers," Kinzler says. "It's certainly the earliest [cell change] we've found so far," agrees White. Both researchers assert that the gene's discovery will improve screening for colon cancer.

Earlier this year, a group headed by Malcolm G. Dunlop of the Medical Research Council's Human Genetics Unit in Edinburgh, Scotland, reported a less specific way to screen members of FAP-prone families. To assess the colon cancer risk of 41 volunteers from seven such families, these researchers looked for a set of six previously discovered "marker" genes thought to lie near the gene causing FAP. Their blood test, called a genetic linkage analysis, yielded accurate positive or negative results for more than two-thirds of the volunteers but was inconclusive for the remaining participants (SN: 2/16/91, p.103).

Dunlop calls the discovery and isolation of the APC gene "an amazing achievement," particularly considering the enormous size of the gene, which consists of more than 8,500 DNA nucleotides. But he cautions that developing a test to detect every possible cancer-causing mutation in such a gene will be "a logistical nightmare."

"There might be 100 different mutations in this gene that could cause cancer," Dunlop says. "It's not time to get rid of linkage studies yet."

Kinzler agrees, but addes that "it should be possible to find all of the mutations eventually." He says he expects that the gene's discovery will ultimately enable researchers to develop drugs that combat colorectal cancer by mimicking the effects of the normal gene, whose function so far remains unknown.
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Title Annotation:gene that causes polyps that may become cancerous discovered
Author:Ezzell, Carol
Publication:Science News
Date:Aug 10, 1991
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