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Gene Screen Could Spot Those at Colon Cancer Risk

About 2% of cases are linked to familial mutation, study finds

WEDNESDAY, May 4, 2005 (HealthDay News) -- Genetic screening for a hereditary form of malignancy among patients already diagnosed with colorectal cancer may help doctors better treat those patients, a new study finds.

It might also help identify family members at heightened risk of the disease.

When Ohio State University researchers conducted routine molecular screening of patients recently diagnosed with colon cancer, they spotted people with a hereditary form of the disease -- known as the Lynch syndrome -- who otherwise would not have been identified.

"This is a good proof of principle that population-based screening may be reasonable," said Dr. Jeffrey Weitzel, director of clinical cancer genetics at City of Hope Comprehensive Cancer Center in Duarte, Calif.

The study appears in the May 5 issue of the New England Journal of Medicine.

According to an accompanying editorial, colorectal cancer is the third most common cause of cancer death in the United States. Some 3 percent to 4 percent of cases are clearly hereditary, including the Lynch syndrome, which involves mutations in specific genes.

Until the genes involved in Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer) were discovered in the early 1990s, doctors relied on the presence of cancer patterns within families, age of onset and certain clinical features of the cancer to detect the syndrome. This method was far from perfect, however. And screening for the actual mutations is difficult and expensive.

There is, in other words, much room for improvement in strategies to diagnose the syndrome.

"We do think that the health benefit from knowing you have a mutation is great," said senior study author Dr. Albert de la Chapelle, a professor of cancer genetics at Ohio State. "Those people who have one of these genetic mutations have almost a 100 percent risk of coming down with cancer and if they know that they have this mutation, clinical surveillance can save their lives."

"The question has been, 'What's the most efficient way to identify all these folks?'" Weitzel said. "We need to do this to be able to watch them or maybe institute preventive measures." People positively identified as having the Lynch syndrome also may benefit from specific treatments, he said.

One possible way to detect the Lynch syndrome is by assessing microsatellite instability, a distinctive change in cellular DNA sequences that occurs in more than 90 percent of these tumors.

Patients with the Lynch syndrome also have protein abnormalities which can be detected with another test called immunohistochemical staining.

The authors of this study had two goals: to see how frequently the Lynch syndrome was present in patients with colorectal cancer and to see which of two screening techniques worked best.

They examined 1,066 men and women recently diagnosed with colorectal cancer at major hospitals in Columbus, Ohio.

Patients first underwent genotyping for microsatellite instability. If they were positive, then they had immunohistochemical staining. Participants were offered genetic testing if they tested positive in either test.

Of the total study participants, 208 (19.5 percent) tested positive for microsatellite instability and, of these, 23 (2.2 percent) had Lynch syndrome mutations.

Fifty-two family members were also found to have Lynch syndrome mutations.

Interestingly, among those with the Lynch syndrome, many did not meet standard guidelines for detecting the disease, such as age and family history.

Based on their findings, the researchers said routine screening would identify more patients with Lynch syndrome, and the two tests were about equal in effectiveness. "Microsatellite instability testing is a somewhat cumbersome procedure, and we think that we have laid the groundwork for a switch to immunohistochemical testing," de la Chapelle noted. The latter test is available in most pathology labs, while the microsatellite instability test is more specialized.

On the basis of their data, the researchers believe about 2 percent (2,960) of the 148,000 American patients diagnosed with colorectal cancer each year carry the mutation for the Lynch syndrome. That means that, among family members, another 8,880 carriers might be identified. Screening of patients with colorectal cancer could provide an opportunity to diagnose 11,840 persons at risk for Lynch syndrome each year in the United States.

An accompanying editorial co-authored by Creighton University's Dr. Henry Lynch, who first described the syndrome, disagreed, however.

"Some people may say that if we find only 2.2 percent being mutation-positive, that this becomes an insignificant contribution to public health, but that is not true," de la Chapelle said. "For every patient with colon cancer that has a mutation, when we look at their families we find several more people who are at the same risk, so we do think that by this sort of screening we could detect virtually thousands of people."

De la Chapelle and his colleagues are expanding the experiment to include all of Ohio. "We hope this will give us a final answer," he said.

More information

For more on Lynch syndrome, visit the National Institutes of Health.

SOURCES: Albert de la Chapelle, M.D., professor, cancer genetics, Ohio State University, Columbus; Jeffrey Weitzel, M.D., director, clinical cancer genetics, City of Hope Comprehensive Cancer Center, Duarte, Calif.; May 5, 2005, New England Journal of Medicine
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