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Updated 10:00 AM October 31, 2005




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U-M scientists say fused genes trigger prostate cancer development


Scientists at the Medical School, in collaboration with researchers at Harvard’s Brigham and Women’s Hospital, have discovered a recurring pattern of scrambled chromosomes and abnormal gene activity that occurs only in prostate cancer.
FISH (fluorescence in situ hybridization) image showing fusion of TMPRSS2 and ETV1 in prostate cancer cells. Probes for ETV1 are in red and probes for TMPRSS2 are in green. Fusion is indicated by the yellow signal indicating gene overlap.
(Photo by Scott Tomlins, U-M Medical School)

In a paper published in the Oct. 28 issue of Science, the research team indicates the chromosomal rearrangements induce specific genes to merge, creating what scientists call a gene fusion. U-M researchers detected the unique molecular signature of the fused genes in the majority of prostate cancer tissue samples they analyzed, but found no evidence of gene fusion in benign prostate tissue or in prostate tissue with non-cancerous changes.

“The data in our study provides tantalizing evidence that gene fusion is the causative agent—the initiating event—in prostate cancer,” says Dr. Arul M. Chinnaiyan, the S.P. Hicks Collegiate Professor of Pathology in the Medical School, who directed the study. “It’s what drives the aberrant over-expression of cancer-causing genes and is the first step in the progression of tissue changes leading to prostate cancer.”

Because this particular gene fusion occurs only in prostate cancer, a diagnostic test to detect in blood or urine the fused genes or their protein products would be specific for prostate cancer and far more accurate than current screening tests, according to Chinnaiyan. And if scientists could find a way to block the gene, it could be the basis for a new, effective treatment for prostate cancer.

According to the American Cancer Society (ACS), more American men will be diagnosed with prostate cancer this year than with any other type of cancer. The ACS estimates in 2005, 232,000 men in the United States will be diagnosed with prostate cancer and 30,350 men will die from the disease. It is the second-most common cause of cancer-related deaths in men.

“Studying gene alterations in prostate cancer is difficult, and as a result there has never been a clear identification of recurrent, non-random genetic rearrangements,” says Jacob Kagan, program director for the Cancer Biomarkers Research Group at the National Cancer Institute (NCI), a sponsor of the research study. “This finding is an important advance, because it suggests that similar mechanisms may be involved in other epithelial cancers, such as breast, lung and colon.”

The abnormal gene fusion associated with prostate cancer occurs when one of two genes, ERGor ETV1, merges with a prostate-specific gene called TMPRSS2. ERGand ETV1are members of the ETS family of transcription factors, which are known to be involved in the development of a bone cancer called Ewing’s sarcoma, and other types of cancer.

While rearrangements in chromosomes and fused genes have been detected in blood cell cancers like leukemia and lymphoma, and in Ewing’s sarcoma, this is the first time they have been found in a common solid tumor like prostate cancer, which develops in epithelial cells lining the prostate gland.

“This is a paradigm shift for all epithelial tumors—such as cancers of the lung, breast, colon, ovary, liver and prostate—which are the most common types of cancer and account for most deaths due to cancer,” says Chinnaiyan, who directs the Bioinformatics Core at the Comprehensive Cancer Center. “We knew gene rearrangements were involved in hematologic malignancies and sarcomas. But finding this recurrent chromosomal rearrangement in prostate cancer suggests that other common epithelial cancers have their own recurrent chromosomal rearrangements. We just haven’t found them yet.”

A bioinformatics analysis method called Cancer Outlier Profile Analysis developed by Scott A. Tomlins and Daniel R. Rhodes, U-M graduate students working in Chinnaiyan’s laboratory, made it possible for the research team to detect extremely high expression levels of outlier genes, including ERGand ETV1, in 132 gene expression microarray datasets and six independent prostate cancer profiling studies.

U-M scientists also used laboratory analysis techniques and gene sequencing to detect gene fusions between TMPRSS2and ERGor ETV1in prostate cancer tissue samples.

“We are especially excited by the profound implications these findings have for the treatment of prostate cancer,” Chinnaiyan says. “It will allow us to categorize prostate tumors by molecular sub-type, which could help determine the most effective treatment for each patient.”

“This collaborative effort has yielded an important molecular biomarker that will help us better detect prostate cancer and ultimately help clinicians determine the risk of dying from the disease,” says Dr. Mark A. Rubin, chief of urologic pathology at Brigham and Women’s Hospital, who also is an associate professor of pathology at Harvard Medical School and a co-author on the paper.

The research was supported by the NCI Early Detection Research Network and Specialized Program of Research Excellence in Prostate Cancer, the ACS, Department of Defense, CCC Bioinformatics Core and the U-M Medical Scientist Training Program.

Additional research collaborators from U-M include Saravana Dhanasekaran, Dr. Rohit Mehra and Sooryanarayana Varambally, research fellows; Xuhong Cao, research associate; Dr. James Montie, the Valassis Professor of Urological Oncology; Dr. Rajal B. Shah, clinical assistant professor of pathology; and Dr. Kenneth J. Pienta, professor of internal medicine and urology.

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