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Genetic mutation, most common in Ashkenazi Jewish population, more than doubles risk of colorectal cancer

ANN ARBOR, MI - A genetic mutation, most often found in people descended from Ashkenazi Jews, can double or even triple the risk of colorectal cancer, according to new data from an international study published in the Sept. 20 issue of Science.

The relationship between mutations in a gene called BLM and increased susceptibility to colorectal cancer was discovered independently by two teams of scientists who analyzed DNA from nearly 3,100 people of Ashkenazi Jewish ancestry living in northern Israel and New York City. The mutation is found in about one percent of individuals descended from a closely related ethnic group, called Ashkenazi Jews, who formerly lived in Eastern Europe.

"When this mutation is inherited from both parents, it causes a serious disorder called Bloom syndrome, which greatly increases an individual's predisposition to cancer," said Stephen B. Gruber, M.D., Ph.D., director of clinical cancer genetics at the University of Michigan's Comprehensive Cancer Center and first author of the Science paper.

"Until now, carriers of one mutant copy were thought to have no increased cancer risk. But our data show that people who inherit the mutation from just one parent face a two- to three-times greater risk for colorectal cancer," Gruber added.

The Israeli data in the Science paper are the first to be published from the Molecular Epidemiology of Colorectal Cancer (MECC) study - a collaboration between Gruber and Gad Rennert, M.D., Ph.D., of the Technion-Israel Institute of Technology Faculty of Medicine and Carmel Medical Center in Haifa, Israel. Rennert also directs the Clalit Health Services National Cancer Control Center in Israel and is the corresponding author of the Science paper.

New York data for the study were collected independently by scientists at Memorial Sloan-Kettering Cancer Center working under the direction of Kenneth Offit, M.D., and Nathan A. Ellis, Ph.D. When the scientific teams discovered they had complementary results, they decided to publish jointly in one paper.

Although the mutation can be detected with DNA analysis, Gruber stressed that it is too soon for DNA tests to be used as a screening tool or a guide to treatment. "Before a discovery like this can move into patient care, others must confirm the findings," Gruber said.

Colorectal cancer is the leading cause of deaths from cancer in Israel and the second leading cause of cancer deaths in the United States. Over 2,000 people are diagnosed with colorectal cancer in Israel each year, but incidence rates vary widely among different ethnic groups. Nearly 150,000 U.S. residents were diagnosed with colorectal cancer in 2002.

A companion paper in the same issue of Science, by researchers at the University of Cincinnati, showed that transgenic laboratory mice designed to carry the human BLM mutation have the same increased risk of cancer.

The results show the value of combining molecular genetics with traditional epidemiology in cancer research - according to Rennert, who chairs the Technion's department of community medicine and epidemiology and directs the MECC's field research in Israel.

"Most genetic studies are based on a small number of samples from one hospital or one laboratory, but the problem is the researcher doesn't see the whole picture that way," Rennert said. "The only way to evaluate the real importance of a finding is to measure it in the general population. In the MECC study, we include every person in a defined geographic area with colorectal cancer. Then we find a control subject without colorectal cancer who matches each patient's demographics as closely as possible. This is extremely difficult to do, but it takes the bias out of your sample and gives you reliable data."

Rennert and Gruber's goal is to understand the interactions between genetic and environmental factors involved in colorectal cancer. "We understand genes aren't the whole story," said Gruber, an assistant professor of internal medicine in the U-M Medical School and an assistant professor of epidemiology in the U-M School of Public Health. "Some people with a genetic susceptibility develop the disease, while others do not. Understanding the role of diet, physical activity, medications and other lifestyle factors will help us learn how to modify the risk of developing the disease."

While their results provide new insight into the complex causes of colorectal cancer, Rennert and Gruber stressed that it won't change how the disease is diagnosed or treated, until the results are confirmed by other scientists. "However, the fact that our collaborators in New York independently came upon the same discovery in humans at almost exactly the same time is encouraging," said Gruber. "It is also significant that University of Cincinnati researchers confirmed the same result in mice."

The MECC study is funded by the National Cancer Institute, with additional funding from the Irving Weinstein Foundation.

Additional U-M members of the research team include Joseph D. Bonner, senior programmer/analyst; Joel K. Greenson, M.D., associate professor of pathology; and research assistants Karen K. Scott and Lynn P. Tomsho.


Written by: Sally Pobojewski


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