- Email: [email protected]
555 PTEN GENE MUTATION AND PRIMARY PROSTATE CANCER PROGRESSION
e218
THE JOURNAL OF UROLOGY姞
analysed. Immunohistochemistry using specific anti-PITX2 antibodies was performed on clinical samples and tissue microarrays of experimental and clinical samples. Effect of PITX2 expression in PC3 cells on cellular motility was investigated through over-expression and knockdown studies. RESULTS: The tumours formed by the PC3 cell line expressed PITX2 at ⬃40 fold higher levels than the LNCaP tumours. Comparison of clinical tissue samples showed incremental expression with the progression from normal to primary to metastatic prostate cancer with bone metastasis samples expressing ⬃13000 times higher levels. This pattern was maintained at the protein level. Functional characterisation of PC3 with PITX2 over-expression and knockdown lines led to increased and decreased cell motility, respectively. CONCLUSIONS: These data indicate a pivotal role for PITX2 in prostate cancer cellular motility and suggest that elevated PITX2 may contribute to poor clinical outcomes in prostate cancer. The pathways implicated in PITX2 function include the canonical Wnt pathway, normally associated with embryological development but also implicated in multiple forms of cancer, and the non-canonical Wnt pathway, which is increasingly implicated in cellular movement and events such as epithelial to mesenchymal transition (EMT) in cancer. With further investigation, PITX2 may develop into an important new therapeutic target in the prevention or treatment of metastatic disease and possibly also serve as a prognostic biomarker for cancer progression or clinically significant disease. Source of Funding: Australasian Urological Foundation Scholarship Queensland Government Growing The Smart State PhD Funding Program NHMRC Project Grant 455907 NHMRC Project Grant 276415
555 PTEN GENE MUTATION AND PRIMARY PROSTATE CANCER PROGRESSION Sepehr Salem*, Abdolrasoul Mehrsai, Amirreza Abedi, Maedeh Rezaeidanesh, Golamreza Pourmand, Tehran, Iran INTRODUCTION AND OBJECTIVES: PTEN is a putative tumor suppressor gene located on 10q23 in prostate cancers, the second most common cause of cancer-related death in men. The PTEN mutation rate is not exactly determined, especially in Asian people. This study sought to further clarify the role of PTEN gene in combination with Gleason scoring for better prediction of progression and survival of cancer. METHODS: Fifty-one cases of primary prostate cancer were studied and followed for at least 5 years. The methods of tissue microdissection and single-strand conformational polymorphism (PCRSSCP analysis) were used. PTEN gene characteristics were compared with the clinicopathological results. RESULTS: Fifty-seven, twenty-one and twenty-two percents of the tumors were Gleason score (GS) ⬍7, 7 and ⬎7 respectively. In addition, the stages of the tumors in 51 primary prostate cancers were IIa(27.5%), IIb(7.8%), IIc(43.1%) and IV(21.6%). Six of fifty-one (11.6%) primary prostate cancers showed mutations in PTEN, which involved exons 1, 2 and 5. The stages of the tumors with positive mutations were 16.7%(IIa), 33.3%(IIb) and 50%(IV). Of them 16.7% and 83.3% were GS ⫽7 and ⬎7 respectively. Five of six patients died as a result of metastases. Patients with a positive mutation of PTEN had a significantly greater GS (P ⬍ .001), lower survival rate (P ⫽ .001), higher tendency to metastasis (P ⫽ .002), and higher prostatespecific antigen (P ⫽ .03). Cox proportional hazard model showed that only GS was significantly correlated with mortality (P ⫽ .03). CONCLUSIONS: Prostate cancer with positive PTEN mutation has a worse prognosis, greater proclivity to metastase, with higher stage and grade. However, this mutation cannot predict the prognosis and the GS is a more precise factor. Source of Funding: None
Vol. 183, No. 4, Supplement, Sunday, May 30, 2010
556 THE EFFECT OF TESTOSTERONE TREATMENT ON PROSTATE HISTOLOGY AND APOPTOSIS IN MEN WITH LATE-ONSET HYPOGONADISM Ozan Efesoy*, Duygu Apa, Selahittin C ¸ ayan, Mersin, Turkey INTRODUCTION AND OBJECTIVES: Very limited studies suggest that there is no conclusive evidence testosterone replacement therapy (TRT) increases risk of prostate cancer and prostate enlargement. The aim of this study was to investigate the effect of TRT on prostate histology and apoptosis in men with late-onset hypogonadism (LOH). METHODS: The study population consisted of 31 consecutive men having LOH with prostate specific antigen (PSA) level of 4 ng/ml or less. All patients underwent transrectal ultrasound guided prostate biopsy at baseline. Of the patients, 4 were excluded due to prostate cancer in 2, atypical small acinar proliferation in one and prostatic intraepithelial neoplasia in one. Of the 27 patients who received testosterone undecanoate treatment, 12 completed one year of therapy, and prostate biopsy was repeated. Prostate histology and apoptotic index were compared before and after TRT. RESULTS: The mean age of the patients was 57.92⫾4.77 years (range 47 to 65). The mean serum total testosterone significantly increased from 171 to 506 ng/ml (p⫽0.001). No significant differences were observed in serum total and free PSA level (p⫽ 0.418 and 0.939, respectively), prostate volume (p⫽0.635) and maximal urinary flow rate (p⫽0.912). The table shows prostate histology and apoptotic index before and after TRT in all patients. To investigate if there is any risk for cancer development, because prostate cancer commonly occurs in the peripheral zone, there were no significant differences in apoptotic index, epithelial/stromal cells ratio and atrophy score of peripheral zone before and after TRT. CONCLUSIONS: This study demonstrated that TRT did not affect serum PSA level, prostate volume and maximal urinary flow rate. This study also suggests that TRT does not cause the risk for prostate cancer development because of increase in apoptotic index and atrophy score, and decrease in epithelial/stromal cells ratio of peripheral zone. Before treatment
After treatment
P value
Transitional zone apoptotic index (%)
14.78⫾5.20
8.78⫾3.07
0.390
Peripheral zone apoptotic index (%)
4.38⫾1.69
8.13⫾3.52
0.356
Transitional zone epithelial/stromal cells
43.33⫾4.71
34.44⫾4.44
0.169
Peripheral zone epithelial/stromal cells
27.50⫾4.53
25.00⫾3.27
0.649
Transitional zone atrophy score (%)
7.00⫾3.26
22.22⫾10.10
0.146
Peripheral zone atrophy score (%) 5.53⫾2.57 13.75⫾5.95 0.160 Table: Prostate histology and apoptotic index before and after testosterone undecanoate treatment for one year.
Source of Funding: None
557 INDUCTION OF TUMOR SUPPRESSOR GENES IL24 AND IL32 BY MICRORNA-205 IN PROSTATE CANCER. Shahana Majid*, Altaf Dar, Sharanjot Saini, Yi Chen, Varahram Shahryari, Jan Liu, Saif Zaman, Hiroshi Hirata, Soichiro Yamamura, Koji Ueno, Gaurav Khatri, Peter Carroll, Rajvir Dahiya, San Francisco, CA INTRODUCTION AND OBJECTIVES: MicroRNAs are small noncoding RNAs that regulate the expression of approximately 30% of all human genes, either inhibiting target mRNA translation or inducing its degradation. These genes are abnormally expressed in human
THE JOURNAL OF UROLOGY姞
analysed. Immunohistochemistry using specific anti-PITX2 antibodies was performed on clinical samples and tissue microarrays of experimental and clinical samples. Effect of PITX2 expression in PC3 cells on cellular motility was investigated through over-expression and knockdown studies. RESULTS: The tumours formed by the PC3 cell line expressed PITX2 at ⬃40 fold higher levels than the LNCaP tumours. Comparison of clinical tissue samples showed incremental expression with the progression from normal to primary to metastatic prostate cancer with bone metastasis samples expressing ⬃13000 times higher levels. This pattern was maintained at the protein level. Functional characterisation of PC3 with PITX2 over-expression and knockdown lines led to increased and decreased cell motility, respectively. CONCLUSIONS: These data indicate a pivotal role for PITX2 in prostate cancer cellular motility and suggest that elevated PITX2 may contribute to poor clinical outcomes in prostate cancer. The pathways implicated in PITX2 function include the canonical Wnt pathway, normally associated with embryological development but also implicated in multiple forms of cancer, and the non-canonical Wnt pathway, which is increasingly implicated in cellular movement and events such as epithelial to mesenchymal transition (EMT) in cancer. With further investigation, PITX2 may develop into an important new therapeutic target in the prevention or treatment of metastatic disease and possibly also serve as a prognostic biomarker for cancer progression or clinically significant disease. Source of Funding: Australasian Urological Foundation Scholarship Queensland Government Growing The Smart State PhD Funding Program NHMRC Project Grant 455907 NHMRC Project Grant 276415
555 PTEN GENE MUTATION AND PRIMARY PROSTATE CANCER PROGRESSION Sepehr Salem*, Abdolrasoul Mehrsai, Amirreza Abedi, Maedeh Rezaeidanesh, Golamreza Pourmand, Tehran, Iran INTRODUCTION AND OBJECTIVES: PTEN is a putative tumor suppressor gene located on 10q23 in prostate cancers, the second most common cause of cancer-related death in men. The PTEN mutation rate is not exactly determined, especially in Asian people. This study sought to further clarify the role of PTEN gene in combination with Gleason scoring for better prediction of progression and survival of cancer. METHODS: Fifty-one cases of primary prostate cancer were studied and followed for at least 5 years. The methods of tissue microdissection and single-strand conformational polymorphism (PCRSSCP analysis) were used. PTEN gene characteristics were compared with the clinicopathological results. RESULTS: Fifty-seven, twenty-one and twenty-two percents of the tumors were Gleason score (GS) ⬍7, 7 and ⬎7 respectively. In addition, the stages of the tumors in 51 primary prostate cancers were IIa(27.5%), IIb(7.8%), IIc(43.1%) and IV(21.6%). Six of fifty-one (11.6%) primary prostate cancers showed mutations in PTEN, which involved exons 1, 2 and 5. The stages of the tumors with positive mutations were 16.7%(IIa), 33.3%(IIb) and 50%(IV). Of them 16.7% and 83.3% were GS ⫽7 and ⬎7 respectively. Five of six patients died as a result of metastases. Patients with a positive mutation of PTEN had a significantly greater GS (P ⬍ .001), lower survival rate (P ⫽ .001), higher tendency to metastasis (P ⫽ .002), and higher prostatespecific antigen (P ⫽ .03). Cox proportional hazard model showed that only GS was significantly correlated with mortality (P ⫽ .03). CONCLUSIONS: Prostate cancer with positive PTEN mutation has a worse prognosis, greater proclivity to metastase, with higher stage and grade. However, this mutation cannot predict the prognosis and the GS is a more precise factor. Source of Funding: None
Vol. 183, No. 4, Supplement, Sunday, May 30, 2010
556 THE EFFECT OF TESTOSTERONE TREATMENT ON PROSTATE HISTOLOGY AND APOPTOSIS IN MEN WITH LATE-ONSET HYPOGONADISM Ozan Efesoy*, Duygu Apa, Selahittin C ¸ ayan, Mersin, Turkey INTRODUCTION AND OBJECTIVES: Very limited studies suggest that there is no conclusive evidence testosterone replacement therapy (TRT) increases risk of prostate cancer and prostate enlargement. The aim of this study was to investigate the effect of TRT on prostate histology and apoptosis in men with late-onset hypogonadism (LOH). METHODS: The study population consisted of 31 consecutive men having LOH with prostate specific antigen (PSA) level of 4 ng/ml or less. All patients underwent transrectal ultrasound guided prostate biopsy at baseline. Of the patients, 4 were excluded due to prostate cancer in 2, atypical small acinar proliferation in one and prostatic intraepithelial neoplasia in one. Of the 27 patients who received testosterone undecanoate treatment, 12 completed one year of therapy, and prostate biopsy was repeated. Prostate histology and apoptotic index were compared before and after TRT. RESULTS: The mean age of the patients was 57.92⫾4.77 years (range 47 to 65). The mean serum total testosterone significantly increased from 171 to 506 ng/ml (p⫽0.001). No significant differences were observed in serum total and free PSA level (p⫽ 0.418 and 0.939, respectively), prostate volume (p⫽0.635) and maximal urinary flow rate (p⫽0.912). The table shows prostate histology and apoptotic index before and after TRT in all patients. To investigate if there is any risk for cancer development, because prostate cancer commonly occurs in the peripheral zone, there were no significant differences in apoptotic index, epithelial/stromal cells ratio and atrophy score of peripheral zone before and after TRT. CONCLUSIONS: This study demonstrated that TRT did not affect serum PSA level, prostate volume and maximal urinary flow rate. This study also suggests that TRT does not cause the risk for prostate cancer development because of increase in apoptotic index and atrophy score, and decrease in epithelial/stromal cells ratio of peripheral zone. Before treatment
After treatment
P value
Transitional zone apoptotic index (%)
14.78⫾5.20
8.78⫾3.07
0.390
Peripheral zone apoptotic index (%)
4.38⫾1.69
8.13⫾3.52
0.356
Transitional zone epithelial/stromal cells
43.33⫾4.71
34.44⫾4.44
0.169
Peripheral zone epithelial/stromal cells
27.50⫾4.53
25.00⫾3.27
0.649
Transitional zone atrophy score (%)
7.00⫾3.26
22.22⫾10.10
0.146
Peripheral zone atrophy score (%) 5.53⫾2.57 13.75⫾5.95 0.160 Table: Prostate histology and apoptotic index before and after testosterone undecanoate treatment for one year.
Source of Funding: None
557 INDUCTION OF TUMOR SUPPRESSOR GENES IL24 AND IL32 BY MICRORNA-205 IN PROSTATE CANCER. Shahana Majid*, Altaf Dar, Sharanjot Saini, Yi Chen, Varahram Shahryari, Jan Liu, Saif Zaman, Hiroshi Hirata, Soichiro Yamamura, Koji Ueno, Gaurav Khatri, Peter Carroll, Rajvir Dahiya, San Francisco, CA INTRODUCTION AND OBJECTIVES: MicroRNAs are small noncoding RNAs that regulate the expression of approximately 30% of all human genes, either inhibiting target mRNA translation or inducing its degradation. These genes are abnormally expressed in human