When Good Genes Go Bad

New evidence ties gene fusion to prostate cancer

Could scrambled genes cause prostate cancer? Arul M. Chinnaiyan (M.D. and Ph.D. 1999), the S.P. Hicks Collegiate Professor of Pathology in the U-M Medical School, thinks so.

Arul Chinnaiyan and Scott Tomlins Photo: Martin Vloet

In a research study published in the October 28, 2005, issue of Science, scientists in Chinnaiyan’s laboratory reported a recurring pattern of mixed-up chromosomes and abnormal gene activity that was found only in prostate cancer. The rearranged chromosomes caused specific genes to merge, creating what scientists call a gene fusion.

“We found tantalizing evidence that gene fusion is the causative agent — the initiating event — in prostate cancer,” says Chinnaiyan. “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 the fused genes or their protein products in a patient’s blood or urine would be specific for prostate cancer and far more accurate than current screening tests. And if scientists could find a way to block the fused genes, it could be the basis for a new, effective treatment for prostate cancer.

Every year, more American men are diagnosed with prostate cancer than with any other type of cancer. The American Cancer Society estimated that, in 2005, 232,000 men in the United States would be diagnosed with prostate cancer and 30,350 men would die from the disease. It is the second-most common cause of cancer-related deaths in men.

This FISH (fluorescence in situ hybridization) image shows fused genes in prostate cancer cells. Fusion is indicated by the yellow signal indicating gene overlap. Photo: Scott Tomlins, U-M Medical School

While similar 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.

“It 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 U-M Comprehensive Cancer Center. “We knew gene rearrangements were involved in hematologic malignancies and sarcomas. But finding this recurrent pattern 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 the 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 the signature of fused genes in prostate tissue.

“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.”

Research leading to the gene fusion discovery was supported by the National Cancer Institute.

—Sally Pobojewski

For an expanded version of the story:
www.med.umich.edu/opm/newspage/2005/fusedgene.htm

For patient information on prostate cancer:
www.cancer.med.umich.edu/learn/prostate.htm