Mar. 27, 2006 Researchers at Mayo Clinic have narrowed the search for effective prostate cancer biomarkers (genetic variations that point to a specific disease or condition), identifying changes in the expression of genes of the whole genome closely correlated to prostate cancer development and progression. They also showed that DNA hypermethylation (DNA modification without changing sequence) plays a significant role in these processes.
"This is good news in an area where our ability to diagnose and predict has previously been less than stellar," said Krishna Donkena, Ph.D., Mayo Clinic urologic researcher. "Our only tool is the PSA test, which has little predictive value. These findings move us much closer to a more accurate test."
The search to identify biomarkers that can be translated into affordable and effective medical tests can be complicated. Prostate cancer causes differential expression of hundreds of different genes, each potentially an indicator of whether a man may get the disease, or already has it. They also may be used to provide information on the development of the cancer, without the need for a painful tumor biopsy.
When seeking to narrow their search to a manageable level, the researchers analyzed 32 cancerous and eight benign patient-tissue samples using genome microarrays representing 33,000 human genes. The information they gleaned from this analysis allowed them to identify 624 differentially-expressed genes between cancerous and benign tissue. They validated these findings in the original 40 tissue samples as well as in 32 additional samples (20 cancerous, 12 benign). The results showed eight genes with significant under-expression and three with significant over-expression, strongly implicating them in prostate cancer development and progression.
Over the years, research has shown that DNA methylation is commonly linked to the development and progression of cancers. This epi-genetic alteration results in silencing or seriously inhibiting gene expression, which in turn lessens the body's ability to defend against cancer. Current research has not done enough to discover ways to convert this information into a useful medical test, in large part due to the limited number of genes that have been thoroughly studied, and their insufficient sensitivity and specificity (probability of getting a true positive or true negative) for prostate cancer detection.
Dr. Donkena's team looked at 62 cancerous and 36 benign tissue samples to assess the degree of methylation in the three previously identified under-expressed genes, comparing two known methylated genes. They determined that one gene, PDLIM4, had hypermethylation that could serve as an effective sensitivity marker, accurately detecting prostate cancer 95 percent of the time. The researchers further determined that the combined measurement of a previously known gene, GSTP1, and PDLIM4 improved the detection rate to 98 percent.
Prostate cancer is the second leading cause of cancer death for men in the United States, exceeded only by lung cancer. The sooner a cancer can be diagnosed, the better treatment outcomes will be, so Dr. Donkena and her colleagues are constantly looking for ways to predict who will get prostate cancer, as well as to find better ways to diagnose early or even prevent this disabling and often fatal disease. "We hope that in addition to being a valuable diagnostic and prognostic tool, our discoveries about these genes will help us develop new treatments for prostate cancer," she said.
Other Mayo researchers involved in this study include Karla Ballman, Ph.D.; Bruce Morlan; John Cheville, M.D.; Roxann Neumann; Michael Lieber, M.D.; Donald Tindall, Ph.D.; and Charles Young, Ph.D.
Results of their study were published in the Feb. 15 issue of Clinical Cancer Research.
This research was funded by grants from the National Institutes of Health and is the result of ongoing studies conducted under the auspices of a National Cancer Institute (NCI) SPORE grant -- Specialized Programs of Research Excellence. Mayo Clinic currently is working on projects under six SPORE grants: breast, brain, lymphoma, myeloma, pancreas and prostate cancer.
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