BERKELEY, CA (UroToday.com) - Researchers at Queen’s University in Kingston, Canada, led by Dr. Jeremy Squire, have identified a possible cause for the loss of PTEN, a tumor suppressor gene that can lead to the development of more aggressive forms of prostate cancer.
PTEN is one in a small class of tumor suppressor genes that closely regulates the growth of cells. When PTEN is altered or deleted in prostate cells, they lose the ability to make a protein that controls normal growth. Cells can then grow in an uncontrolled manner in the gland and they can develop into a prostate cancer. There is compelling evidence from Dr. Squire’s group (Yoshimoto M, Br J Cancer 2007; 97: 678-85; Sirkar K, J Pathol 2009 218:505-13) and from investigators at the Royal Marsden Hospital in London (Reid AH, Br J Cancer2010;102:678–684) that the loss of PTEN by chromosome deletion carries an unfavorable prognosis in prostate cancer.
This new discovery about how PTEN deletions actually take place gives urologists a greater understanding of how aggressive prostate cancer develops, because we now have some insight into the mechanism by which the PTEN gene is destroyed. In the study, they examined cancerous tissue samples from 330 radical prostatectomy samples and determined that the loss of the PTEN gene occurred in ~40% of tumors by chromosome deletion, and typically the DNA breaks occurred close to a large, unstable segment of the genome close to the PTEN gene. Their discovery suggests that proximity of PTEN to this region makes cancer-suppressing genes more prone to being deleted or inactivated in prostate cancer.
Dr. Squire and his colleagues discovered the PTEN gene deletions using the four color FISH gene-detection technology that his laboratory has developed and customized for detection of tumor suppressor gene losses in formalin fixed paraffin embedded tissue sections. FISH (fluorescence in situ hybridization) is a cytogenetic technique developed by biomedical researchers in the early 1980s that has been used to detect and localize the presence or absence of specific DNA sequences in chromosomes. FISH is now a mainstay technique for analysis of genomic biomarkers by molecular pathology service providers such as Bostwick Laboratories. Dr. Squire developed this new four-color approach using an optimal combination of FISH probes, close to the PTEN gene, specifically for use on tissue sections. The probe set includes flanking genes either side of PTEN (WAPAL and FAS) and this combination significantly improves on the process of identifying PTEN losses, and reduces the percentage of cells with “false positive” losses of part of their nucleus due to sectioning cuts.
This new approach to recognizing PTEN deletions has the potential to lead to a better treatment of prostate cancer patients. Studies that we are performing at Bostwick laboratories demonstrate that PTEN four color FISH can be reliably performed with 2µm section of prostate biopsy.
Prostate cancer with a Gleason score of 6 and 7 comprises 60% to 80% of prostate cancer. The majority of these cancers can be managed conservatively. Bostwick Laboratories provides biomarker studies for prostate cancer patients to assist urologists and patients with additional tools for making a decision to forego conservative (watchful waiting) versus aggressive treatments (prostatectomy and radiation treatment). Presence or absence of PTEN deletion is the most important biomarker study available at the present time.
Our experience with 1,200 cases of prostate cancer with Gleason score 6 and 7 shows PTEN deletions in ~18% of the cases. Of these PTEN deleted cases ~ 44% also showed the TMPRSS2-ERG gene fusion protein in the cell nuclei.
Presence of these biomarkers will warrant an aggressive management, i.e. PTEN deletion and TMPRSS2-ERG fusion. Converse absence of these biomarkers (80% of cancers) may be managed with a conservative approach in combinations with other clinical parameters such serum PSA level, PSA velocity, monograms, etc.
Written by:
Deloar Hossain, MD* as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
*Medical Director
Molecular Diagnostics
Bostwick Laboratories
7001 Lake Ellenor Drive
Orlando, FL 32809
Tel: 407-992-0997 Ext-4118
Fax: 407-992-0989
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