ANN ARBOR, Mich. – Using the power of advanced DNA microarray technology, scientists at the University of Michigan Medical School have identified a gene that triggers production of large amounts of a specific protein in cancerous prostate cells. Because the protein is present only in malignant cells and is easily visible when stained, it could improve the accuracy and sensitivity of screening tests for prostate cancer – the second leading cause of cancer-related deaths in men.
The protein is an enzyme involved in fat metabolism called a-methylacyl-CoA racemase, or AMACR for short. AMACR has never before been associated with any type of cancer – according to Mark A. Rubin, M.D., and Arul M. Chinnaiyan, M.D., Ph.D., the scientists who directed the U-M research study. Results will be published in the April 3 issue of the Journal of the American Medical Association.
“We detected high levels of AMACR protein in over 95 percent of more than 300 prostate tissue samples that contained localized cancer,” says Chinnaiyan, an assistant professor of pathology in the U-M Medical School. “Equally important, we found no AMACR protein in benign prostate tissue or in tissue with non-malignant cell changes. We then evaluated the clinical utility of AMACR immunostaining on 94 prostate needle biopsies; the sensitivity and selectivity ratings were 97 percent and 100 percent.”
“AMACR is one of approximately 20 genes which we found to be over-expressed consistently in prostate cancer,” Chinnaiyan adds. “This doesn’t mean that these genes cause prostate cancer, but they can be a marker or indicator of prostate cancer for diagnostic or prognostic purposes.”
AMACR’s accuracy and specificity is a major improvement over the Prostate Specific Antigen (PSA) test – the only diagnostic screening test currently available to physicians. “The beauty of AMACR is that it is cancer-specific and found only in malignant cells,” says Rubin, an associate professor of pathology and surgery in the U-M Medical School. “PSA can’t differentiate between cell changes caused by cancer and those caused by benign changes in the prostate. As a result, PSA tests have a high rate of false positives, which can mean repeat needle biopsies and unnecessary surgery.”
U-M researchers say AMACR could act as a diagnostic marker for other types of cancer, too. When Rubin and Chinnaiyan surveyed cells from different types of cancer looking for AMACR over-expression, they found it in colorectal, prostate, ovarian, breast, bladder, lung, renal cell, lymphoma and melanoma – with the highest amounts present in colorectal and prostate cancer.
Research on the genetic and molecular profile of prostate cancer using DNA microarray analysis is part of a major initiative underway in the U-M’s Comprehensive Cancer Center. Its goal is to link molecular genetics with clinical outcome for all types of cancer.
“By looking at gene expression, we can learn so much more about a tumor,” says cancer center director Max Wicha, M.D., U-M Distinguished Professor of Oncology, and a professor of internal medicine. “It explains why one patient’s tumor remains localized, while another tumor spreads. It will allow us to tailor specific therapies to the gene expression profile of each patient.”
“Previous prostate cancer studies focused on one gene at a time,” Chinnaiyan says. “With DNA microarray technology, we can look at thousands of genes in prostate cells simultaneously. This is important, because it is most likely that many genes are involved in the development and progression of prostate cancer – each controlling a different step in the process.”
In previous work leading to the AMACR discovery, researchers at the U-M Comprehensive Cancer Center analyzed more than 80 complementary DNA microarrays to assess gene expression profiles in four types of tissue.
These included normal prostate tissue from men with and without prostate cancer, tissue with benign changes, localized prostate cancer and aggressive, metastatic cancer. Tissue samples were obtained from the U-M Prostate Specialized Program of Research Excellence (SPORE) tumor bank, funded by the National Cancer Institute and directed by study co-author Kenneth Pienta, M.D., a professor of internal medicine and surgery in the U-M Medical School.
Since genetic and molecular profiling compares genes and proteins from normal cells to those from malignant cells in various stages, the U-M is developing other comprehensive tissue banks, so the technology can be applied to more types of cancer – including lung, ovarian, breast and colorectal cancer.
In future research, Rubin and Chinnaiyan plan to look for AMACR in a much larger number of prostate tissue samples from U-M and other institutions with SPORE tumor banks. They are starting a prospective clinical trial to test the reliability of AMACR testing against traditional surgical pathology diagnostic procedures. Eventually, they hope to develop a blood test for AMACR, eliminating the need for needle biopsies of the prostate.
This research was supported by the National Cancer Institute and the U-M Bioinformatics Program. The U-M has applied for a patent on prostate cancer gene expression profiles for future diagnostic and therapeutic use.
Other U-M scientists involved in the study include: Ming Zhou, M.D., Ph.D., a house officer in pathology; Saravana M. Dhanasekaran, Ph.D., and Sooryanarayana Varambally, Ph.D., research fellows; Terrence R. Barrette, research associate; Martin G. Sanda, M.D., associate professor of surgery and of internal medicine; and Debashis Ghosh, Ph.D., assistant professor of biostatistics in the U-M School of Public Health.
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