http://repub.eur.nl/res/aut/16195/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/33848/ 2011-07-01T00:00:00Z http://repub.eur.nl/res/pub/33779/ 2011-05-01T00:00:00Z BACKGROUND FGFR3 mutations are associated with a good clinical disease course in bladder tumors. Currently, prognostic markers to stratify prostate cancer (PCa) patients for conservative management are lacking. Conflicting results have been found on the presence of FGFR3 mutations in PCa. Our objective was to determine the prevalence of FGFR3 mutations in a subset of prostate tumors. Next, determine the prevalence of FGFR3 mutations in PCa patients with coexistent tumors in other tissues. METHODS Primary and locally advanced prostate tumors (n = 132) were collected at our medical center. From the 132 PCa patients, 28 (21%) were diagnosed with coexistent primary tumors (bladder, skin, pancreas, renal cell, gastric, colon, hepatic, and lung). Tumors were analyzed by FGFR3 mutation analysis on exon 7, 10, and 15, known to harbor the most frequent mutations. RESULTS The prevalence of FGFR3 mutations in patients with only PCa was 0%. Most PCa patients presented with coexistent bladder (n = 12) and bladder and skin tumors (n = 7). Other coexistent tumors in PCa patients included: bladder and pancreatic cancer (n = 1); bladder and renal cell carcinoma (n = 1); bladder and gastric carcinoma (n = 1); skin cancer (n = 1); colon cancer (n = 3); hepatic carcinoma (n = 1); and lung cancer (n = 1). FGFR3 mutations were detected in 9/15 (60%) analyzed bladder tumors. CONCLUSIONS FGFR3 mutations were absent in the investigated prostate tumors, suggesting a minor role of these mutations in tumorigenesis. Hence, FGFR3 mutation analysis is not suitable to select patients for conservative management. Interestingly, if a prostate tumor coincided with other tumors these were mostly bladder and skin. http://repub.eur.nl/res/pub/22532/ 2011-02-18T00:00:00Z The prostate is a walnut-sized gland that is located caudally from the urinary bladder. It excretes fluid as a part of the semen of men. Prostatic neoplasia is common; in Western developed countries prostate cancer is the most common non-cutaneous malignancy in men and it is the second leading cause of all male cancer deaths. The detection of prostate cancer has markedly increased since the introduction of the serum prostatespecifi c antigen (PSA) in the late eighties. Although familial and hereditary prostate cancer occurs, sporadic cancers account for at least 85% of all prostate cancers. Age is the strongest risk factor for developing prostate cancer. From autopsy studies it is known that in the 6th decade already 55% of the male population has the disease, and more than 75% of men older than 85 years have cancer foci in their prostate. Prostate cancer is a very heterogeneous disease that can range from indolent, asymptomatic tumours in many patients to a rapidly fatal malignancy in some. At diagnosis, the majority of tumours are confined to the prostatic gland, named clinical stage cT1 and cT2 (see Table 1 for the Tumour, Node, Metastasis (TNM) classifi cation). Some tumours, however, already grow outside the prostatic capsule (cT3) or even invade the surrounding organs (cT4). Dissemination of the disease usually occurs to the regional pelvic lymph nodes and the axial skeleton. The latter will mainly cause pain, although neurological deficit due to compression of the myelum is also possible in severe cases. Diagnostic modalities to detect prostate cancer are digital rectal examination (DRE), measurement of the serum prostate-specific antigen (PSA), transrectal ultrasound of the prostate (TRUS) with subsequent ultrasound-guided prostate biopsies, and magnetic resonance imaging (MRI). Computerized tomography (CT) of the pelvis is reserved for detection of enlarged lymph nodes, whereas bone metastases can be detected by nuclear scintigraphy, CT, MRI or conventional X-ray of the skeleton. The serum PSA is a marker for prostate cancer. Although PSA lacks specificity, it is currently the most valid biomarker available, not only for diagnostic purposes but also for disease monitoring after treatment with curative intent. Since its introduction, PSA has been widely used as a screening tool to detect prostate cancer in asymptomatic men. Recent findings showed that PSA-based screening for prostate cancer resulted in a relative risk reduction of 20% to die from the disease. It must be noted, however, that at the time of the first statistical relevant difference between the intervention and control arm, it was shown that 48 patients had to be treated to prevent one death from prostate cancer. The findings by Schroder et al. show the difficulties that remain to correctly identify the indolent prostate tumours from the ones that need curative treatment. Therefore, prognostic markers that facilitate a risk stratification of prostate cancer patients and that are helpful for optimizing treatment decisions are still very much needed. http://repub.eur.nl/res/pub/19770/ 2010-05-01T00:00:00Z Background:The phosphatidylinositol 3-kinase (PI3K)-AKT pathway is activated in many cancers. Mutational hotspots in AKT1 and in the regulatory and catalytic subunits of PI3K have been detected in multiple tumour types. In AKT1, the E17K substitution leads to a PI3K-independent activation of AKT1.Methods:A mutational profiling of AKT1 and of the mutational hotspots in PIK3CA and PIK3R1 was carried out in samples from primary and recurrent prostate tumours.Results:We show that, in prostate cancer, AKT1(E17K) had a prevalence of 1.4%. The mutation seemed to be associated with a favourable clinical course but it was not associated with a specific tumour growth pattern. Activating mutations in PIK3CA or PIK3R1 were not found in prostate cancer.Conclusion:The E17K substitution in AKT1 is rare in prostate cancer. It seems associated with a favourable clinical outcome but not with a specific histology of the tumour. http://repub.eur.nl/res/pub/27945/ 2010-05-01T00:00:00Z Background: Fusion of the androgen-regulated gene transmembrane protease, serine 2, TMPRSS2, to the v-ets erythroblastosis virus E26 oncogene homolog (avian), ERG, of the erythroblast transformation-specific (ETS) family is the most common genetic alteration in prostate cancer (PCa). Objective: To determine whether expression of androgen-regulated TMPRSS2-ERG predicts response to endocrine treatment in hormone-naïve, node-positive PCa. Design, setting, and participants: Eighty-five patients with histologically confirmed, node-positive PCa who were without treatment at the moment of lymph node dissection were analysed. RNA was isolated from the paraffin-embedded lymph node metastases and complementary DNA (cDNA) was made. The quality of cDNA was tested by polymerase chain reaction (PCR) analysis of the expression of the housekeeping gene hydroxymethylbilane synthase, HMBS (formerly PBGD). TMPRSS2-ERG expression was analysed by PCR using a forward primer in TMPRSS2 exon 1 and a reverse primer in ERG exon 4. Measurements: The primary end point was time from start of endocrine therapy to the occurrence of three consecutive rises in prostate-specific antigen (PSA) that were at least 2 wk apart and resulted in two 50% increases over the PSA nadir. Secondary end points were time to PSA nadir after start of endocrine treatment and cancer-specific and overall survival. Results and limitations: TMPRSS2-ERG was expressed in 59% of the 71 patients who could be analysed. Median duration of response to endocrine therapy was 20.9 mo versus 24.1 mo for gene fusion-positive versus gene fusion-negative patients (95% confidence intervals: 18.6-23.1 vs 18.9-29.4, p = 0.70). Furthermore, no significant differences were seen between the two groups for the secondary end points. Conclusions: Expression of TMPRSS2-ERG is frequent in lymph node metastases of patients with untreated PCa; however, expression of this androgen-regulated fusion gene did not correspond with duration of response to endocrine therapy. Our results suggest that expression of TMPRSS2-ERG is not a candidate marker to select for metastatic PCa patients who will benefit more from endocrine treatment. http://repub.eur.nl/res/pub/25269/ 2009-10-15T00:00:00Z Purpose: To gain insight in the mechanism and clinical relevance of TMPRSS2-ERG expression in prostate cancer,wedetermined the specific characteristics of fusion transcripts starting at TMPRSS2 exon 1 and at a more upstream and less characterized exon 0. Experimental Design: We used quantitative PCR analysis to investigate expression of wild-type TMPRSS2(exon 0) and TMPRSS2(exon 1) and of ERG fusion transcripts. Expression was tested in normal tissue samples, in prostate cancer cell lines and xenografts, and in fresh-frozen clinical prostate cancer samples (primary tumors and recurrences). Expression in clinical samples was correlated with disease progression. Results: TMPRSS2(exon 0) and TMPRSS2(exon 1) transcripts were similarly androgen regulated in prostate cancer cell lines, but the expression levels ofTMPRSS2(exon 1)were much higher. Comparison of expression in different tissues showed TMPRSS2(exon 0) expression to be much more prostate specific. In androgen receptor-positive prostate cancer xenografts, TMPRSS2(exon 1) transcripts were expressed at similar levels, but TMPRSS2(exon 0) transcripts were expressed at very variable levels. The same phenomenon was observed for TMPRSS2-ERG fusion transcripts. In clinical prostate cancers, the expression of TMPRSS2(exon 0)-ERG was even more variable. Expression of TMPRSS2 (exon 0)-ERG transcripts was detected in 55% (24 of 44) of gene fusion-positive primary tumors but only in 15% (4 of 27) of gene fusion-positive recurrences and at much lower levels. Furthermore, in primary tumors, expression of TMPRSS2(exon 0)-ERG transcripts was an independent predictor of biochemical progression-free survival. Conclusion: The expression of TMPRSS2(exon 0)-ERG fusion transcripts in prostate cancer is associated with a less-aggressive biological behavior. http://repub.eur.nl/res/pub/14151/ 2008-12-01T00:00:00Z OBJECTIVE: To correlate the histopathological characteristics of lymph node metastases in prostate cancer with cancer-specific survival (CSS). PATIENTS AND METHODS: The histopathological slides from 142 patients who had had a pelvic lymph node dissection for node-positive prostate cancer were reviewed. For each patient we recorded the number of lymph nodes removed, the number of positive nodes, the diameter of the largest metastasis and extranodal extension (ENE). The lymph node metastases were graded according to the Gleason system. These variables were correlated with CSS. RESULTS: The mean age of the patients was 62.4 years and the mean preoperative prostate-specific antigen level was 40.2 ng/mL. The median follow-up was 77.5 months, and the median overall and CSS were 91 and 112 months, respectively. On univariable analysis the following variables correlated with poor CSS: a nodal Gleason score of >7 (hazard ratio 2.4, P < 0.001), a diameter of the largest metastasis of >3 mm (2.2, P = 0.025), more than two lymph node metastases (2.0, P = 0.003), and ENE in more than one lymph node (1.9, P = 0.014). Multivariable analysis showed only the nodal Gleason score and the diameter of the largest metastasis to be independent predictors of CSS (1.8, P = 0.021, and 2.2, P = 0.046, respectively). CONCLUSION: The histopathological characteristics of lymph node metastases in prostate cancer have predictive value for the clinical outcome. The nodal Gleason score and the diameter of the largest metastasis are independent predictors of survival. http://repub.eur.nl/res/pub/29084/ 2008-12-01T00:00:00Z http://repub.eur.nl/res/pub/14456/ 2008-09-15T00:00:00Z In this study, we describe the properties of novel ETV1 fusion genes, encoding N-truncated ETV1 (dETV1), and of full-length ETV1, overexpressed in clinical prostate cancer. We detected overexpression of novel ETV1 fusion genes or of full-length ETV1 in 10% of prostate cancers. Novel ETV1 fusion partners included FOXP1, an EST (EST14), and an endogenous retroviral repeat sequence (HERVK17). Like TMPRSS2, EST14 and HERVK17 were prostate-specific and androgen-regulated expressed. This unique expression pattern of most ETV1 fusion partners seems an important determinant in prostate cancer development. In transient reporter assays, full-length ETV1 was a strong transactivator, whereas dETV1 was not. However, several of the biological properties of dETV1 and full-length ETV1 were identical. On stable overexpression, both induced migration and invasion of immortalized nontumorigenic PNT2C2 prostate epithelial cells. In contrast to dETV1, full-length ETV1 also induced anchorage- independent growth of these cells. PN T2C2 cells stably transfected with dETV1 or full-length ETV1 expression constructs showed small differences in induced expression of target genes. Many genes involved in tumor invasion/metastasis, including uPA/uPAR and MMPs, were up-regulated in both cell types. Integrin β3 (ITGB3) was clearly up-regulated by full-length ETV1 but much less by dETV1. Based on the present data and on previous findings, a novel concept of the role of dETV1 and of full-length ETV1 overexpression in prostate cancer is proposed. http://repub.eur.nl/res/pub/35540/ 2007-03-01T00:00:00Z Objectives: To investigate the contribution of urodynamically proven presence or absence (International Continence Society classification) of bladder outlet obstruction (BOO) to treatment recommendations for lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia, and to investigate the impact of the replacement of the invasively estimated BOO classification with the noninvasively assessed BOO probability on treatment recommendations. Methods: Mandatory tests, recommended tests, and pressure-flow studies (with BOO classification) were performed in 150 consecutive men with LUTS suggestive of BPH. Three experienced urologists proposed, independently of each other, the treatment for each patient: watchful waiting, pharmacologic treatment, or surgery. After repeat randomization of the patients and replacement of the BOO classification with the BOO probability, the procedure was repeated 1 month later. A third treatment proposal was done after repeat randomization and after replacement of the BOO probability with the BOO classification. Results: The symptom score and quality-of-life score were the most decisive in the treatment recommendations, followed by the BOO probability and BOO classification. The medical history, physical status, and duration of the complaints did not significantly affect the treatment recommendations. The intraindividual agreement between the judgments that included the BOO classification and the judgments that included the BOO probability was comparable to the agreement between both judgments that included BOO classification. The interindividual agreement between the judgments that included the BOO classification was not significantly different from that of the judgments that included the BOO probability. Conclusions: The symptom score and quality-of-life score were the most decisive in the medical treatment recommendations, followed by the BOO probability and BOO classification. The noninvasively assessed BOO probability was as valuable as the invasively estimated BOO classification in the medical treatment recommendations.