“We have known that not all BPH is the same; patients experience different degrees of prostate enlargement and experience different symptoms, ranging from none to renal failure, but we didn’t know why,” said Robert Getzenberg, Ph.D., director of urological research and associate professor, department of urology, University of Pittsburgh School of Medicine and co-director of the prostate and urologic cancer program of the University of Pittsburgh Cancer Institute (UPCI). “In fact, we knew little about the causes of BPH, and prior to this study, we knew very little about the genetics of BPH. As a result, we were treating all patients in a similar manner, which proved to be very costly and, in many patients, ineffective. Now, we can look into targeting the different types of BPH and creating new therapies to alleviate the symptoms of the disease based upon their unique properties.”
Researchers identified a set of 511 genes that were differentially expressed in tissue samples taken from four groups of patients: normal (patients without BPH), BPH without symptoms, BPH with symptoms, and BPH with cancer. Principal component analysis (PCA) showed that each of the four groups were clearly distinguishable from one another. The prostates of the group of men with symptomatic BPH were most similar to the BPH areas of the individuals with prostate cancer. This relationship may indicate the presence of a potential link between BPH and prostate cancer that has not been previously identified as well as support the concept of a genetic “field effect” in individuals with prostate cancer.
"Studying patterns of gene expression is a powerful tool. Already it is providing important clues about the fundamental nature of disease which will allow us to more strategically target our therapies," said Joel B. Nelson, M.D., professor and chairman of the department of urology at the University of Pittsburgh School of Medicine and co-director of the Comprehensive Prostate and Urologic Cancer Program at UPCI.
Further analysis showed that there were unique sets of genes that serve as a signature of each of the groups. Genes associated with cell proliferation were up regulated in the symptomatic BPH group. A series of genes including oncogenes were up regulated in the BPH cancer group. A cluster of genes with unknown function distinguished the asymptomatic BPH from the others.
“One of the most striking of these discoveries is the strong correlation between inflammation and symptomatic BPH. With this information, we can now investigate new therapeutic approaches, such as using anti-inflammatory agents to alleviate symptoms. This is a key finding because previously, we were using a few drugs that were effective only in a small population and now, we may be able to stratify our treatments and diagnostics to better treat patients,” said Dr. Getzenberg.
Subsets of genes including inflammatory mediators, cytokines and extracellular matrix associated molecules distinguished the symptomatic BPH and BPH with cancer from the normal and asymptomatic groups.
The study also found that JM27, a gene up regulated in prostate cancer and specific to the prostate and female reproductive tissues, was up regulated in symptomatic BPH, suggesting that overexpression of JM27 may be involved in the progression of BPH, prostate cancer and tumors of the female reproductive tract.
BPH is one of the most common diseases affecting men. More than half of all men over the age of 60, and 80 percent by age 80, will have enlarged prostates. Forty to 50 percent will develop symptoms of BPH, which include more frequent urination, urinary tract infections, the inability to completely empty the bladder, and, in severe cases, the eventual damage of the bladder and kidneys.
This study was completed as a collaborative effort between the University of Pittsburgh, GeneLogic Inc. of Gaithersburg, Md., and the Kagawa Medical University, Kagawa, Japan.
CONTACT:
Jocelyn Uhl
UhlJH@msx.upmc.edu
Clare Collins
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Journal
Proceedings of the National Academy of Sciences