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U-M CCC - Progress Newsletter Winter 2003 Online

Research Roundup

A red flag for lethal prostate cancer

High levels of activity in a gene called EZH2 could be a warning sign of metastatic prostate cancer, according to scientists at the U-M Cancer Center.

In an article published in the Oct. 10 issue of Nature, U-M scientist Arul M. Chinnaiyan, M.D., Ph.D., and his research team used advanced DNA microarray technology to show that EZH2 expression was at "the top of the list"of 55 genes found to be more active in metastatic prostate cancer than in localized prostate cancer. This is the first study linking EZH2 to solid tumors, according to Dr. Chinnaiyan.

When the EZH2 gene is active, the cell uses its coded instructions to produce EZH2 protein. U-M scientists believe a future diagnostic test for high levels of this protein could serve as a red flag for physicians and help save the lives of men with the most dangerous form of the disease.

"We found the greatest EZH2 over-expression in metastatic prostate cancer tissue. At this point, it's unclear whether the gene plays a role in cancer's development or is simply an indicator of lethal progression," says Dr. Chinnaiyan, an assistant professor of pathology and urology in the U-M Medical School.

EZH2 is one of several related proteins that controls a cell's genetic memory and interferes with transcription - the process cells use to transcribe or copy their genetic code.

If additional research and human clinical trials confirm the U-M results, a test for EZH2 protein could, for the first time, allow physicians to identify accurately those men who need immediate, aggressive treatment to prevent the cancer from spreading outside the prostate. Once prostate cancer metastasizes, or spreads, to other organs, it is usually incurable.
"Over the past 50 years, there has been no significant improvement in clinical outcome for men diagnosed with advanced prostate cancer and no way to tell ahead of time which cancers will spread and which cancers will remain localized," says Mark A. Rubin, M.D., a former U-M faculty member, who is at Dana Farber Harvard Cancer Center. "It is exciting to think that we may have finally found something to help the 30,000 men who die every year from metastatic prostate cancer."

This research was supported by the National Cancer Institute, CaPCURE and the U-M Prostate Specialized Program of Research Excellence (SPORE).

Read the complete news release.

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

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," says Stephen B. Gruber, M.D., Ph.D., director of clinical cancer genetics at the U-M 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," Dr. Gruber adds.

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 Dr. 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. Dr. 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. 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, Dr. Gruber stresses 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," Dr. Gruber says.

Colorectal cancer is the leading cause of deaths from cancer in Israel and the second leading cause of cancer deaths in the United States. The researchers'goal is to understand the interactions between genetic and environmental factors involved in colorectal cancer.

"We understand genes aren't the whole story," says Dr. Gruber. "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."

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

Read the complete news release.

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