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Genetic Defect Calls for Colon Cancer Screening

Risk lower in those with familial risk minus the mutation, study finds

TUESDAY, April 26, 2005 (HealthDay News) -- Researchers have found a way to ease the burden of screening for people considered to be at high risk of colorectal cancer and other malignancies because of a suspected genetic defect.

These people must now undergo frequent testing because their family history indicates that they have a syndrome called hereditary nonpolyposis colorectal cancer (HNPCC). But perhaps half of those who meet the familial criteria for a common form of HNPCC don't have the genetic defect that causes the condition, claims a report in the April 27 issue of the Journal of the American Medical Association.

All 3,422 members of the 161 families in the study met the criteria for that form of HNPCC, called Amsterdam-I, said study author Dr. Noralane M. Lindor, a consultant in medical genetics at the Mayo Clinic. But those criteria are based entirely on family history, she noted.

The new study looked at tissue samples and found that many family members did not have the genetic defect that limits the body's ability to repair the genetic damage that underlies HNPCC. "Those that carried the defect did have a high risk of cancer," Lindor said. "The group that had the pedigree, but not the defect, did not have the same high degree of risk of cancer."

Currently, HNPCC is defined entirely on the basis of family history, she explained. A person with three close relatives who have colon cancer, at least one under the age of 50, with the cancer appearing in two different generations is defined as having the condition.

Persons in the study who met those family criteria but did not have the genetic defect still had a "moderately elevated" risk of colorectal cancer, but not as great as those with the genetic defect. Also, they did not have the elevated risk of other forms of cancer -- stomach, ovarian, and others -- as those with the genetic defect.

People with the family history but not the genetic defect should still have more frequent screening tests than members of the general population, with testing for colorectal cancer started five to 10 years before the earliest age at which the cancer was diagnosed in the family, Lindor said, "but we can back off on some of the more stringent screening."

"The real news is that we can look at the tumor and do risk assessment, and counsel that family differently," she stated.

The finding points up the increased role of genetics in cancer diagnosis and screening, said Dr. Durado Brooks, director of the colorectal cancer program for the American Cancer Society.

"When HNPCC was initially described, about 15 years ago, we had only clinical criteria," he said. "As we understand the genome better, we now have a more sophisticated level of testing and understanding, seeing that things we initially lumped together actually are different types of disease."

However, the entire genetic story of familial colorectal cancer is still unknown, Brooks noted.

"It is still unusual for a family to have clusters of cases of colon cancer," he said. "So the likelihood is that there is a genetic mutation that we have not identified."

Another report in the same issue of the journal provided support for the current guidelines used to screen patients for HNPCC, which accounts for 1 percent to 3 percent of all colorectal cancers.

Those Bethesda guidelines, named for the site where they were determined, call for testing to look for abnormalities called microsatellite instability and mutations in two genes, MSH2 and MLH1, which cause HNPCC. The Bethesda guidelines state that if those abnormalities are found, more detailed tests for mutations should be done.

The guidelines were used in a study of 1,222 newly diagnosed colorectal cancer patients from 20 hospitals in Spain. "Our results demonstrate that the revised Bethesda guidelines constitute a very useful approach to select patients at risk for HNPCC," according to the report published by physicians at the University of Barcelona.

More information

Recommendations for colorectal screening are laid out by the Mayo Clinic.

SOURCES: Noralane M. Lindor, M.D., consultant, medical genetics, Mayo Clinic, Rochester, Minn.; Durado Brooks, M.D., director, colorectal cancer, American Cancer Society, Atlanta; April 27, 2005, Journal of the American Medical Association
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