Prostatecancer (PCa) is a major mortality cause for men around the world and therefore there is a high demand for reliable diagnostic solutions. Prostate-specific antigen (PSA) is currently the representative biomarker for pre-screening of PCa, necessarily followed by biopsy examinations for confirmatory diagnosis. In the biomedical market, equipment to detect PSA in its relevant clinical concentration is already commercialized. These devices are accurate, but the bench-top systems are bulky, expensive, have a long response time, and rely on optical labels. To eliminate these drawbacks, point-of-care (POC) devices are under development, aiming at cost-effective, precise, portable, disposable and environmentally friendly designs with a fast response time. Most of the devices are utilizing conventional biosensing principles. However, the miniaturization of these approaches directly induces performance variations and a drastic decrease of the sensing accuracy. It is noteworthy that no biomarker is ideal, and no definite diagnostic decision can be based on a single biomarker. Thus, the detection of a combination of various biomarkers is recommended to provide multi-variable information for accurate diagnosis in the early stage of cancer development. Some biomarkers are more specific for PCa than others, but of a relatively low concentration in the clinical samples. Therefore, new biosensing concepts with multiplexing capability are under intensive investigation.
Prostatecancer (PCa) is the most frequently diagnosed malignant tumor and the second-leading cause of cancer- related death in men in developed countries 1 – 3 . Patients diagnosed at an early, organ-confined stage can mostly be cured by radical prostatectomy or radiotherapy. However, many patients still present with or progress to metastatic disease 4 , 5 , and palliative androgen deprivation therapy (ADT) in combination with the chemothera- peutic agent docetaxel or the androgen-receptor-signaling inhibitors abiraterone or apalutamide is the standard treatment for this condition 6 – 10 . Virtually all patients acquire resistance to ADT after one to ten years progressing to castration-resistant prostatecancer (CRPC), for which several life-prolonging palliative treatment options are available 11 . In addition to its reliance on androgen receptor signaling from organ-confined to metastatic, castration-resistant disease 12 , 13 , other hallmarks of PCa are its multifocality 14 , its multiclonality 15 , 16 and its notable inter- and intraindividual heterogeneity 17 – 20 ; due to these qualities, PCa management is a major challenge, and thus, further elucidation of the unique biology of this disease is urgently needed. The unique microenvironment (known as the “tumor microenvironment” or “TME”) of the prostate concerning its cellular constitution and the concentration of cytokines, growth factors and hormones is an important factor in PCa development and open
Abstract: The idea of using metabolic aberrations as targets for diagnosis or therapeutic intervention has recently gained increasing interest. In a previous study, our group discovered intriguing differences in the oxidative mitochondrial respiration capacity of benign and prostatecancer (PCa) cells. In particular, we found that PCa cells had a higher total respiratory activity than benign cells. Moreover, PCa cells showed a substantial shift towards succinate-supported mitochondrial respiration compared to benign cells, indicating a re-programming of respiratory control. This study aimed to investigate the role of succinate and its main plasma membrane transporter NaDC3 (sodium-dependent dicarboxylate transporter member 3) in PCa cells and to determine whether targeting succinate metabolism can be potentially used to inhibit PCa cell growth. Using high-resolution respirometry analysis, we observed that ROUTINE respiration in viable cells and succinate-supported respiration in permeabilized cells was higher in cells lacking the tumor suppressor phosphatase and tensin-homolog deleted on chromosome 10 (PTEN), which is frequently lost in PCa. In addition, loss of PTEN was associated with increased intracellular succinate accumulation and higher expression of NaDC3. However, siRNA-mediated knockdown of NaDC3 only moderately influenced succinate metabolism and did not affect PCa cell growth. By contrast, mersalyl acid—a broad acting inhibitor of dicarboxylic acid carriers—strongly interfered with intracellular succinate levels and resulted in reduced numbers of PCa cells. These findings suggest that blocking NaDC3 alone is insufficient to intervene with altered succinate metabolism associated with PCa. In conclusion, our data provide evidence that loss of PTEN is associated with increased succinate accumulation and enhanced succinate-supported respiration, which cannot be overcome by inhibiting the succinate transporter NaDC3 alone.
Androgen deprivation therapy (ADT) remains a key approach in the treatment of prostatecancer (PCa). However, PCa inevitably relapses and becomes ADT resistant. Besides androgens, there is evidence that thyroid hormone thyroxine (T4) and its active form 3,5,3 0 -triiodo-L-thyronine (T3) are involved in the progression of PCa. Epidemiologic evidences show a higher incidence of PCa in men with elevated thy- roid hormone levels. The thyroid hormone binding protein μ-Crystallin (CRYM) medi- ates intracellular thyroid hormone action by sequestering T3 and blocks its binding to cognate receptors (TR α/TRβ) in target tissues. We show in our study that low CRYM expression levels in PCa patients are associated with early biochemical recurrence and poor prognosis. Moreover, we found a disease stage-specific expression of CRYM in PCa. CRYM counteracted thyroid and androgen signaling and blocked intra- cellular choline uptake. CRYM inversely correlated with [18F]fluoromethylcholine (FMC) levels in positron emission tomography/magnetic resonance imaging of PCa patients. Our data suggest CRYM as a novel antagonist of T3- and androgen- mediated signaling in PCa. The role of CRYM could therefore be an essential control mechanism for the prevention of aggressive PCa growth.
Androgen receptor (AR) signaling is required for prostatecancer (PCa) onset as well as development to the more aggressive stage named castration-resistant prostatecancer (CRPC). Targeting AR represents the mainstay strategy to treat PCa, however, since it has a time- limited efficacy identification of AR down-stream effectors with an essential role in mediating AR-signaling is necessary to improve PCa diagnosis, prognosis and medical care. In this work, the AR cistrome has been investigated with particular emphasis on the link between AR and the non-coding RNAs known as microRNAs (miRNAs) that recently have popped-out as powerful regulators of gene expression and being involved in carcinogenesis. In detail, it has been demonstrated that AR binds to miR-22 and miR-29a and induces their expression significantly in prostatecancer cells following androgen stimulation. Intriguingly, miR-22 and miR-29a act as tumor suppressive miRNAs modulating two cancer-associated transcripts, LAMC1 and MCL1, respectively. Indeed, their levels are reduced in primary prostate tumor samples via epigenetic silencing of the genomic regions harboring AR regulatory elements.
ACS, American Cancer Society; ASR, Age-standardized rate; AUA, American Urological Association; BvDU, Professional Association of German Urologists (Berufsverband der Deutschen Urologen); BPH, benign prostatic hyperplasia; DEGAM, German College of General Practice and Family Medicine (Deutsche Gesellschaft für Allgemeinmedizin und Familienmedizin); EAU, European Association of Urology; ERSPC, European Randomized Study of Screening for ProstateCancer; GP, General practitioner; NCCN, National Comprehensive Cancer Network; ng/mL, nanograms per milliliter; PCa, prostatecancer; PLCO, Prostate, Lung, Colorectal and Ovarian study; PSA, pros- tate-speci ﬁc antigen; USPSTF, US Preventive Services Task Force.
Other transgene mouse models used in the scientific community consist of PTEN knockout mice and one might imply these to be more suitable in reflecting human disease. It is indisputably true, that PTEN functions as a master regulator of the PI3K/Akt/mTOR axis and plays an important role in prostatecancer progression. Its role in prostate CSC maintenance, however, is less well acknowledged, partly due to the routine use of PTEN driven prostatecancer models (63, 65, 136). Besides, PTEN loss has been shown to be a late event in prostate carcinogenesis, correlated to metastatic and advanced disease, but not early-stage tumors (137, 138). We propose that loss of PTEN function is not essential for human (prostate) cancer stem cell development and might even be detrimental for stem cell functions and maintenance as proposed before (139). Our results in PTEN expressing PCa models suggest that expression of PTEN and its effects on PI3K signaling may be essential for homeostasis in subsets of prostate CSCs, as this was already shown to be true for hematopoietic stem cells (140).
The aging of population increases the incidence of prostatecancer (PCa) because the median age of PCa patients being diagnosed is 67. Estimation has been made that in the US nearly a quarter-million PCa cases emerged in 2012 accounting for 29% of the total new cancer cases . In contrast, 28,170 patients died of PCa composing only 9% of the total cancer related death . This difference is probably because most of the PCa patients were identified in the early stages and therefore could be cured with local therapies, such as prostatectomy, radiation and cryotherapy, with the five-year survival approaching 100% . However, for advanced metastatic cases these treatments show little benefit and without effective control the patients ineluctably die. Androgen deprivation and chemotherapy are currently standard treatments for these patients. However, after long term application nearly all patients are no longer sensitive to these treatments. Progression or relapse happen even under the circumstance that the plasma concentrations of testosterone are suppressed to around 50 ng/dL by castration or gonadotropin-releasing hormone (GnRH) analogues, while the effects of the remaining androgens are blocked by androgen receptor (AR) antagonists. This situation is termed as castration-resistant prostatecancer (CRPC), which has been mis-comprehended as “androgen independent”. However, recent research revealed that CRPC is still driven by hormones . Many possible mechanisms have been proposed for CRPC, such as super-sensitivity of tumor cells to low levels of androgen, intratumoral androgen para-/autocrine production, AR mutation and ligand independent AR activation. Since 2010, six drugs have been approved for the treatment of CRPC. These drugs either show improvement on overall survival or relieve the symptoms regarding bones, which are the most frequent sites that metastases happen due to the abundant growth factors facilitating the proliferation of cancer cells . More drug candidates are currently under evaluation in different stages of clinical trials and some novel strategies have also been proposed aimed at further potentiation of antitumor effects or reduction of side effects and complications related to treatments.
Resistance to chemotherapy is a major hurdle in prostatecancer (PCa) treatment. Although chemotherapeutic treatments typically display initial benefit, cancer cells frequently acquire novel characteristics that will render these cells unresponsive to current cytotoxic treatments. Docetaxel (Taxotere, Sanofi-Aventis, Paris, France) is a microtubule-stabilizing agent that is clinically approved for a range of malignancies, including castration- resistant PCa (CRPC) for which it is the standard-of-care and prolongs survival of patients ( Tannock et al. 2004 ). Unfortunately, tumors inevitably progress due to the acquired docetaxel resistance ( O’Neill et al. 2011 ). In addition, docetaxel resistance is often accompanied with a cross-resistance, i.e., dampened efficacy of other antitumor therapeutics and conversely, the use of other therapeutic agents, e.g., antiandrogens, appears to be associated with the emergence of resistance to docetaxel ( van Soest et al. 2014 ). Therefore, identifi- cation of the underlying molecular mechanisms of docetaxel resistance is of a pivotal importance to combat docetaxel resistance in clinics ( Madan et al. 2011 ).
Purpose The aim of the present meta-analysis was to quantify effects of resistance exercise (RE) on physical performance and function, body composition, health-related quality of life (HRQoL), and fatigue in patients with prostatecancer. Methods Trial data were obtained from the databases PubMed, MEDLINE, EMBASE, SCOPUS, and the Cochrane Library as of inception to 31st of December 2016. Thirty-two trials with 1199 patients were included. Results that were measured by using the same assessment method in five or more of the original studies were pooled in a meta- analysis.
In this prospective study of 2727 cases of prostatecancer, the consumption of protein and calcium derived from dairy foods were significantly positively associated with risk. Strengths of the EPIC study are its prospective design, the large number of prostatecancer cases and the wide range of animal food intakes. We were also able to consider other possible risk factors such as education, marital status, alcohol intake, height, weight, energy intake, smoking and physical activity. Data on PSA use in the EPIC cohort are not available, but the annual rates of PSA testing in middle aged men within some of the participating countries suggest relatively low rates, of 6% in England and Wales, 7% in the Netherlands, 9% in Spain and 16% in Italy, compared with approximately 38% in white Americans (Etzioni et al, 2002; Paez et al, 2002; Otto et al, 2003; D’Ambrosio et al, 2004; Melia et al, 2004).
We should also emphasize that in the study in focus, nutrition was not associated with risk factors. However, other studies should be conducted due to the importance of micronutrients for genetic stability. Considering cancer as a multifactorial genetic disease, with strong influences of age, ethnicity, socioeconomic factors, lifestyle, family history, micronutrients and epigenetic factors associated with occupational and environmental risk, the findings obtained in this epidemiological study corroborate as the main risk factors that guide the etiology of prostatecancer. The results obtained can be used as indicators of public policies related to the treatment and prevention of prostatecancer.
Even though bone metastases in prostatecancer display a predominantly osteoblastic appearance, osteolytic changes usually precede bone formation, and elevated bone breakdown remains a dominant feature of metastatic prostatecancer . Inhibition of bone degradation with anti-resorptive medications has been shown to significantly delay skeletal-related events in patients with advanced prostatecancer, emphasizing the fundamental role of bone resorption in the growth even of osteoblastic metastases . Therefore, findings from a predominantly osteolytic cancer cell line such as PC3 are of clinical relevance for the treatment of osteoblastic tumors . According to the literature, it is important to get at least a 50 % inhibition in tumor growth in mouse models in order to predict clinical responses in patients . The presented thesis fulfills this demand, yet, the neutralizing antibody did not stop the osteolytic process. This is not unexpected. Other factors in addition to IL-6 are also involved in bone resorption and in fact, IL-6 maintains many reciprocal interrelations with other pro- resorptive cytokines, forming a whole network in which they often act in synergism .
The management of mCRPC was palliative until 2004, when docetaxel that showed significant survival benefit in patients with mCRPC, was approved (Fitzpatrick, 2012). Nowadays, some agents, including the hormonal therapies abiraterone acetate (approved in 2012), enzalutamide, the immunotherapy agent sipuleucel-T (approved in 2010), the chemotherapy agent cabazitaxel and the newly approved radioactive therapeutic agent Ra 223 dichloride (radium-223), are specific for the treatment of docetaxel-naïve patients with mCRPC. The osteoclast inhibitor zoledronic acid and human monoclonal antibody against receptor activator of nuclear factor κ B ligand (RANKL) denosumab reduce the occurrence of skeletal-related events (SREs, for example; fractures, radiation or surgery to bone, and spinal cord compression) and are useful for patients who have progressed to more advanced stages of prostatecancer. Unfortunately, these costly currently approved survival-prolonging systemic therapies for mCRPC have a median survival gain of not more than 5 months and some serious side effects. Some of the most common adverse effects observed across the therapies include hot flush, fatigue, gastrointestinal symptoms, joint swelling or discomfort, and infections (Shore et al., 2015). Prolonged androgen deprivation therapy (ADT) results in bone demineralization leading to increased fracture risk and subsequent increase in morbidity and mortality (Eastham, 2007). Hypocalcaemia and osteonecrosis of the jaw are concern for ADT and anti-resorptive therapies (zoledronic acid and denosumab). Close monitoring of potential clinical hepatotoxicity should be considered for the first- and second-generation antiandrogens including abiraterone acetate as well as for docetaxel. Nephrotoxicity is a concern for zoledronic acid and cabazitaxel. Cardiovascular events are reported in association with the use of GnRH analogues. Further, neutropenia and hypersensitivity reactions, which include generalized rash or erythema, hypotension, and bronchospasm are a concern for cabazitaxel. Acute phase infusion reactions have been associated with sipuleucel-T with symptoms of fever, chills, respiratory events (dyspnoea, hypoxia, and bronchospasm), nausea, vomiting, fatigue, hypertension, and tachycardia. Severe neurosensory symptoms and localized erythema of the extremities with oedema followed by desquamation, as well as neutropenia have occurred in patients on docetaxel (Shore et al., 2015).
Another well-known effect of PMA is the release of TNFα and other factors from LNCaP cells. Therefore, the question whether bryostatin 1 affects the composition of the conditioned medium (CM) was addressed. Indeed, whereas CM- PMA was capable of inducing apoptosis in naïve LNCaP cells, CM-Bryo1 and, more importantly, CM-Bryo1+PMA failed to induce apoptosis. As with cells that are directly treated with PMA and bryostatin 1, cells that received CM-Bryo1+PMA still exhibited phosphorylation of p38, which was maintained over several hours, as well as phosphorylation of JNK and dephosphorylation of pAkt. Taken together, these data are in favor with the hypothesis that bryostatin 1 prevents PMA from triggering the release of pro-apoptotic factors to the CM, while others are still being secreted and are capable of triggering a cascade that leads ultimately to the phosphorylation of p38 and JNK and dephosphorylation of pAkt, respectively. Although a cytokine array did not reveal any obvious difference in the secretion of pro-apoptotic factors, probably due to issues of sensitivity , a more accurate measurement employing ELISA revealed that PMA-induced secretion of TNFα is essentially blunted by bryostatin 1. PMA, in turn, depends on the autocrine secretion of this cytokine for killing prostatecancer cells . The impaired TNFα secretion by PMA when cells are simultaneously treated with bryostatin 1 seems to fully account for the functional antagonism. Indeed, adding back this cytokine at similar final concentrations as those normally observed in CM-PMA fully restores the apoptotic activity. It is interesting that bryostatin 1 promotes apoptosis and TNFα release from leukemia cells [115, 116], suggesting a strict cell type dependency for the differential killing ability of this agent.
clari ﬁed. DNA copy number alterations have been compre- hensively characterized in prostatecancer, and identiﬁed numerous chromosomal regions of recurrent deletions har- boring known tumor suppressor genes like RB1 at 13q14, CDKN1B at 12p13, or the PTEN gene at 10q23, but the target genes of most other recurrently deleted regions remain to be identiﬁed. Deletion of 5q21 belongs to the most frequent alterations in prostatecancer. After its ﬁrst description in 1995 (4), this alteration has gained considerable interest, as recent studies reported a high deletion frequency (13% –26%), and identiﬁed a small commonly deleted region including the gene encoding chromodomain helicase DNA-binding protein 1 (CHD1; refs. 5–7). Two groups reported independent- ly that CHD1 has tumor-suppressive features in prostatecancer (8, 9). CHD1 is involved in assembly, shifting, and removal of nucleosomes from the DNA double helix to keep it in an open and transcriptionally active state (10). CHD1 is essential to maintain the open chromatin of pluripotent embryonic stem cells (10). CHD1 associates with the promoters of active genes by the cooperative action of its 2 chromodomains, which speci ﬁcally bind to the H3K4-trimethylated histones. Several of the 8 other members of the CHD family have been implicated in cancer before. CHD2 has been suggested as a putative tumor suppressor that might play a role in DNA damage response and lymphoma development (11). Heterozygous frameshift muta- tion or loss of heterozygosity of CHD1, CHD2, CHD3, CHD4, CHD7, and CHD8 have been reported from gastric and colon cancers (12). Mutation of CHD7 was detected in a lung cancer cell line (13). CHD5 is a known tumor suppressor controlling apoptosis via the p19–p53 pathway and which is often inacti- vated by deletions involving the chromosomal band 1p36
Prostatecancer is characterised by structural rearrangements. Most frequently translocations occur between androgen-responsive genes and members of the ETS family. Hereby, the most common translocation is the TMPRSS2:ERG-Fusion. In a recent sequency study we could detect 140 gene fusions without ETS-genes. Hence, aim of the study was to measure the prevalence of some of these non-ets gene fusions. In a randomized study, 27 of the 140 non-ets genes were analyzed by FISH in 500 prostate cancers in tissue microarray regarding chromosomal rearrangements. Using break-apart FISH probes for one fusion partner each, we found rearrangements of 13 (48%) of the 27 analyzed genes in 300-400 analyzable cancers per gene. Recurrent breakage, often accompanied by partial deletion of the genes, was found for NCKAP5,
The aim of this review is to report on the current status of prostate-specific membrane antigen (PSMA)-directed theranostics in prostatecancer (PC) patients. The value of 68 Ga-PSMA-directed PET imaging as a diagnostic procedure for primary and recurrent PC as well as the role of evolving PSMA radioligand therapy (PRLT) in castration-resistant (CR)PC is assessed. The most eminent data from mostly retrospective studies currently available on theranostics of prostatecancer are discussed. The current knowledge on 68 Ga-PSMA PET/CT implicates that primary staging with PET/CT is meaningful in patients with high-risk PC and that the combination with pelvic multi parametric (mp)MR (or PET/mpMR) reaches the highest impact on patient management. There may be a place for 68 Ga-PSMA PET/CT in intermediate-risk PC patients as well, however, only a few data are available at the moment. In secondary staging for local recurrence, 68 Ga-PSMA PET/mpMR is superior to PET/CT, whereas for distant recurrence, PET/CT has equivalent results and is faster and cheaper compared to PET/mpMR. 68 Ga-PSMA PET/CT is superior to 18 F / 11 Choline PET/CT in primary staging as well as in secondary staging. In patients with biochemical relapse, PET/ CT positivity is directly associated with prostate-specific antigen (PSA) increase and amounts to roughly 50% when PSA is raised to ≤0.5 ng/ml and to ≥90% above 1 ng/ml. Significant clinical results have so far been achieved with the subsequent use of radiolabeled PSMA ligands in the treatment of CRPC. Accumulated activities of 30 to 50 GBq of 177 Lu-PSMA ligands seem to be clinically safe with biochemical response and PERCIST/RECIST response in around 75% of patients along with xerostomia in 5 –10% of patients as the only notable side effect. On the basis of the current literature, we conclude that PSMA-directed theranostics do have a major clinical impact in diagnosis and therapy of PC patients. We recommend that 68 Ga-PSMA PET/ CT should be performed in primary staging together with pelvic mpMR in high-risk patients and in all patients for secondary staging, and that PSMA-directed therapy is a potent strategy in CRPC patients when other treatment options have failed. The combination of PSMA-directed therapy with existing therapy modalities (such as 223 Ra-chloride or androgen deprivation ther- apy) has to be explored, and prospective clinical multicenter trials with theranostics are warranted.
effects of that treatment in prostatecancer cells on myeloid cells (Figure 1 a). In the first setup, prostatecancer cells were exposed to the plasma, and the cell culture supernatants were collected after four hours and added to myeloid cells. At 1 h, immediate effects such as ROS production and mitochondrial activity were determined. At 24 h, the metabolic activity and cell proliferation of the myeloid cells were investigated. At 96 h, the cell surface marker expression profile and cytokine release were assessed. In the direct co-culture approach, the prostatecancer cells were exposed to the plasma, and myeloid cells were added 1 h later. The co-cultures were imaged at 24 h, 48 h, 72 h, and 96 h, with an additional investigation of the cell surface marker profile of myeloid cells and the cytokine release in the supernatants of the co-cultures at 96 h. An image of the plasma treatment procedure is shown in Figure 1 b. Based on previous studies, it was hypothesized that the plasma treatment decelerates tumor cell growth. Investigating the impact on the metabolic activity of the cancer cells 4 h after plasma treatment, the treatment led to a significant reduction in both prostatecancer cell lines investigated (Figure 1 c). The plasma labeling denotes cells that were treated with the gas plasma directly. The argon control indicates conditions where the inert argon gas was not ignited into plasma but instead was merely blown onto the cell suspension as a mock treatment to exclude any biological effects of the noble gas alone. Similar to other plasma jets, the kINPen generates ROS in the plasma gas phase that subsequently diffuse into the treated liquid [ 31 ]. From there, the species further diffuse to cells [ 16 ] with some of the species possibly accumulating in the cytosol, as has been suggested for H 2 O 2 passing through aquaporin channels in the membrane [ 32 ]. As the purpose was to investigate the immunomodulatory potential of supernatants from the untreated and plasma-treated prostatecancer cells, we also investigate residual ROS in these suspensions. Only a minor presence of ROS was observed in the plasma-treated LNCaP cultures 1 h after exposure, while residual ROS were absent for plasma-treated PC3 cells at 1 h (Figure 1 d). At 4 h after plasma treatment, supernatants of the prostatecancer cells were collected and used for subsequent experiments with myeloid cells. Altogether, plasma treatment decelerated prostatecancer cell growth, and the majority of plasma-derived ROS have reacted with the cancer cells.
One of the prostatecancer candidate genes is the CYP17 gene. A thymidine (T) to cytosine (C) transition (designated A2 variant) in the promoter region of the CYP17 gene has been used in several studies in order to determine a possible association with the prostatecancer risk. A recent meta-analysis found no effect of the CYP17 polymorphism for the sporadic prostatecancer (74). The question still remained unresolved for familial cases, since only two investigators included prostatecancer families (22;93). In order to evaluate the role of the CYP17 A2 allele in familial aggregation of prostatecancer we performed an association study. A putative influence of the A2 allele on disease risk was investigated by designing a dominant and a recessive model. In our study we realized a slight difference of CYP17 genotypes between sporadic cases and controls. However, this unequal distribution was not significant. Although a certain trend can be seen, that the A2 allele increases susceptibility to prostatecancer, our results are consistent with the conclusion, that CYP17 has no effect on prostatecancer risk in general. To investigate the involvement of this polymorphism in familial prostatecancer we performed comparison of the familial cases with controls. Our results showed no evidence that the CYP17 genotype might predispose for a familial aggregation of prostatecancer neither under the dominant nor under the recessive model. Our results do not suggest a role of CYP17 as a high-risk susceptibility gene for familial prostatecancer nor as a modifier for the disease risk.