Primary Prostate Cancer Cases Research Articles

MLH1 Loss in Primary Prostate Cancer.

Among mismatch repair-deficient (MMRd) prostate cancers, loss of MLH1 is relatively uncommon and few cases have been reported in detail. Here, we describe the molecular features of two cases of primary prostate cancer with MLH1 loss detected by immunohistochemistry, and in one case, confirmed via transcriptomic profiling. Both cases were microsatellite stable on standard polymerase chain reaction (PCR)-based microsatellite instability (MSI) testing, but showed evidence of MSI on a newer PCR-based long mononucleotide repeat (LMR) assay and by next-generation sequencing. Germline testing was negative for Lynch syndrome-associated mutations in both cases. Targeted or whole-exome tumor sequencing using multiple commercial/academic platforms (Foundation, Tempus, JHU, and UW-OncoPlex) showed modestly elevated, though variable, tumor mutation burden estimates (2.3-10 mutations/Mb) consistent with MMRd, but without identifiable pathogenic single-nucleotide or indel mutations in MLH1. Copy-number analysis confirmed biallelic MLH1 loss in one case and monoallelic MLH1 loss in the second case, without evidence of MLH1 promoter hypermethylation in either. The second patient was treated with single-agent pembrolizumab and demonstrated a short-lived prostate-specific antigen response. These cases highlight the challenges in identifying MLH1-deficient prostate cancers using standard MSI testing and commercial sequencing panels, and support the utility of immunohistochemical assays and LMR- or sequencing-based MSI testing for detection of MMRd prostate cancers.

Comprehensive assessment of anaplastic lymphoma kinase in localized and metastatic prostate cancer reveals targetable alterations.

Anaplastic lymphoma kinase (ALK) is a tyrosine kinase with genomic and expression changes in many solid tumors. ALK inhibition is first line therapy for lung cancers with ALK alterations, and an effective therapy in other tumor types, but has not been well-studied in prostate cancer. Here, we aim to delineate the role of ALK genomic and expression changes in primary and metastatic prostate cancer. We determined ALK expression by immunohistochemistry and RNA-Seq, and genomic alterations by NGS. We assessed functional consequences of ALK overexpression and pharmacological ALK inhibition by cell proliferation and cell viability assays. Among 372 primary prostate cancer cases we identified one case with uniformly high ALK protein expression. Genomic analysis revealed a SLC45A3-ALK fusion which promoted oncogenesis in in vitro assays. We observed ALK protein expression in 5/52 (9%) of metastatic prostate cancer cases, of which 4 of 5 had neuroendocrine features. ALK-expressing neuroendocrine prostate cancer had a distinct transcriptional program, and earlier disease progression. An ALK-expressing neuroendocrine prostate cancer model was sensitive to pharmacological ALK inhibition. In summary, we found that ALK overexpression is rare in primary prostate cancer, but more frequent in metastatic prostate cancers with neuroendocrine differentiation. Further, ALK fusions similar to lung cancer are an occasional driver in prostate cancer. Our data suggest that ALK-directed therapies could be an option in selected patients with advanced prostate cancer.

Tenascin C regulates cancer cell glycolysis and tumor progression in prostate cancer.

Tenascin C is a potential biomarker of cancer-associated fibroblasts and has been significantly associated with poor prognosis in patients with prostate cancer. However, the effects of Tenascin C in prostate cancer cell glycolysis largely remain unclear. Thus, this study aimed to investigate the Tenascin C expression in prostate cancer and its correlation to glycolysis-related protein and gene expression, clinicopathological parameters, and survival of patients. We performed immunohistochemical staining for Tenascin C in 141 cases of primary prostate cancer. Based on public data sets, we explored the association of Tenascin C with angiogenesis-related genes, M2 macrophage-related gene, androgen receptor levels, PI3K/AKT/NF-κB pathway genes, and glycolytic enzyme expression. The glucose uptake, lactate production, and glycolytic enzyme levels were detected by glycolysis assay and western blotting. Our results showed that Tenascin C expression is upregulated in prostate cancer tissues compared with benign prostatic hyperplasia tissues. High Tenascin C expression in prostate cancer cells was positively associated with lymph node metastasis, advanced clinical stage, the expression of CD105, CD206, and androgen receptor levels. The Kaplan-Meier curves showed a significant association of Tenascin C expression with the patient's overall survival. Tenascin C expression was positively associated with PI3K p85, pAKT-ser308, and NF-κB p65 protein expression in prostate cancer samples. Moreover, siRNA-mediated knockdown of Tenascin C expression inhibited cell glucose uptake, lactate production, and glycolytic-enzyme expression in prostate cancer cells invitro. Together, our findings suggest that Tenascin C is a prognostic marker for patients with prostate cancer and that its effects might be mediated via regulation of the glycolysis process of prostate cancer cells.

Prognostic role of TSPAN1, KIAA1324 and ESRP1 in prostate cancer

The aim of this study was to validate prostate cancer‐associated genes on transcript level and to assess the prognostic value of the most promising markers by immunohistochemistry. Based on differentially expressed genes found in a previous study, 84 genes were further validated using mRNA expression data and follow‐up information from the Cancer Genome Atlas (TCGA) prostate cancer cohort (n = 497). Immunohistochemistry was used for validation of three genes in an independent, clinically annotated prostatectomy patient cohort (n = 175) with biochemical relapse as endpoint. Also, associations with clinicopathological variables were evaluated. Eleven protein‐coding genes from the list of 84 genes were associated with biochemical recurrence‐free survival on mRNA expression level in multivariate Cox‐analyses. Three of these genes (TSPAN1, ESRP1 and KIAA1324) were immunohistochemically validated using an independent cohort of prostatectomy patients. Both ESRP1 and KIAA1324 were independently associated with biochemical recurrence‐free survival. TSPAN1 was univariately prognostic but failed significance on multivariate analysis, probably due to its strong correlation with high Gleason scores. Multistep filtering using the publicly available TCGA cohort, data of an earlier expression profiling study which profiled 3023 cancer‐associated transcripts in 42 primary prostate cancer cases, identified two novel candidate prognostic markers (ESRP1 and KIAA1324) of primary prostate cancer for further study.

Mapping Isoform Abundance and Interactome of the Endogenous TMPRSS2-ERG Fusion Protein by Orthogonal Immunoprecipitation–Mass Spectrometry Assays

TMPRSS2-ERG gene fusion, a molecular alteration found in nearly half of primary prostate cancer cases, has been intensively characterized at the transcript level. However limited studies have explored the molecular identity and function of the endogenous fusion at the protein level. Here, we developed immunoprecipitation–mass spectrometry assays for the measurement of a low-abundance T1E4 TMPRSS2-ERG fusion protein, its isoforms, and its interactome in VCaP prostate cancer cells. Our assays quantified total ERG (∼27,000 copies/cell) and its four unique isoforms and revealed that the T1E4-ERG isoform accounted for 52 ± 3% of the total ERG protein in VCaP cells, and 50 ± 11% in formalin-fixed paraffin-embedded prostate cancer tissues. For the first time, the N-terminal peptide (methionine-truncated and N-acetylated TASSSSDYGQTSK) unique for the T1/E4 fusion was identified. ERG interactome profiling with the C-terminal, but not the N-terminal, antibodies identified 29 proteins, including mutually exclusive BRG1- and BRM-associated canonical SWI/SNF chromatin remodeling complexes. Our sensitive and selective IP-SRM assays present alternative tools to quantify ERG and its isoforms in clinical samples, thus paving the way for development of more accurate diagnostics of prostate cancer.

Prognosis of primary or metachronous prostate cancer in multiple primary genitourinary cancers; a single center experience with long-term results

Objective This study aims to analyze the challenges, approaches and long-term results of primary or metachronous prostate cancer (PCa) in cases with multiple primary genitourinary cancers. Methodology A total of 17 patients were included in the study. Patients with multiple primary genitourinary cancers were divided into two groups according to the diagnosis of primary or metachronous PCa as group 1 and group 2. Results The median age of patients was similar in both groups. The median smoking status (pack-years) was higher in group 2 than group 1. The median prostate-specific antigen (PSA) level was higher in group 1 than group 2. The median follow-up time from primary to the metachronous tumour was higher in group 1 than group 2. The rate of recurrence in PCa was higher in group 1 than group 2. No statistically significant difference was observed in terms of patients’ age, smoking status, PSA levels at diagnosis of PCa and biochemical recurrence or metastasis between the two groups (p > 0.05) Conclusion Primary PCa cases may progress more aggressively than metachronous PCa cases. Biochemical recurrence and metastasis may be less threatening in metachronous PCa cases than primary cases. Therefore, aggressive treatment can be avoided for metachronous PCa cases.

Co-delivery of AKT3 siRNA and PTEN Plasmid by Antioxidant Nanoliposomes for Enhanced Antiproliferation of Prostate Cancer Cells.

Globally, prostate cancer is the fifth major cancer type and the second leading cause of cancer-related death in men. In 2018, about 1.3 million prostate cancer cases were reported worldwide. It is reported that loss of PTEN (tumor suppressor gene) expression leads to hyperactivation of the PI3K/AKT pathway and thus induces uncontrolled cell proliferation. Loss or mutation in regular PTEN expression is reported to occur in ∼30% of primary prostate cancer cases and ∼65% of metastatic cancer cases. Restoring the PTEN expression could inhibit the PI3K/AKT/mTOR signaling pathway, thus avoid the growth of prostate cancer cells. In this work, we have synthesized a multifunctional nanoliposomal formulation incorporating PTEN plasmid, AKT3 siRNA, and antioxidant cerium oxide nanoparticles (CeNPs). The nanoliposomes were able to successfully internalize in prostate cancer (PC-3) cells, restore the expression of PTEN protein, and knock down AKT3 mRNA. Further, the multifunctional nanoliposomes induce DNA damage and apoptosis in prostate cancer cells. The investigation of the PI3K/AKT/mTOR signaling pathway revealed that PTEN protein and apoptosis-specific proteins are overexpressed, leading to the inhibition of oncoproteins and, thus, prostate cancer.

Prostate carcinoma in African-Americans has miRNA expression and biological markers for aggressive disease.

e16558 Background: African American (AA) men have twice the incidence and mortality in Prostate Cancer (PCa) as compared to non-Hispanic Whites. The identification of a biological basis for this disparity is crucial in providing focused treatment. In this study, we have characterized the pathological features and molecular markers of PCa in AA men. Methods: 91 proctectomies for primary PCa and 23 biopsies for metastatic PCa with their pathological data were retrieved. Tissue microarrays were constructed and the expression of Programmed Cell Death 1 (PD-1), Programmed Death Ligand 1 (PD-L1) and Mismatch Repair (MMR) (MLH1, MSH2, MSH6 and PMS2) proteins was assessed by immunohistochemistry. miRNA expression of 24 cases of primary PCa and adjacent normal prostate tissue from proctectomies was identified by microarray in situ hybridization. Spearman’s rank-correlation was used to correlate variables and p < .05 was considered significant. TargetScan and DIANA analysis software were used to identify modulation in miRNA expression. Results: In a supervised heat map, overall the downregulation of microRNA was more than upregulation in tumor tissue; 11 miRNA were upregulated and 12 were downregulated, with a log fold change of 1.5. miR-345, a component of the mismatch repair and DNA Replication pathway, showed significant up-regulation (p = 9.4E-02); has been linked to more aggressive PCa. PD-L1 expression was lower in primary PCa (16%) than in metastatic PCa (35%). PD-1 expression was high in almost half of primary and metastatic PCa patients. MMR protein expression was largely intact in both primary and metastatic PCa cases. Both of these protein markers have been associated with biochemical recurrence and low survival. Conclusions: The biological characteristics (low expression of PD-L1, high expression of PD-1, intact MMR and distinct miRNA signature) identified in our cohort of exclusively AA men are indicators of aggressive PCa. These results explain the biological basis of widely documented poor prognosis of PCa in AA men.

Prostate-specific loss of UXT promotes cancer progression.

Ubiquitously-expressed, prefoldin-like chaperone (UXT) also called Androgen Receptor Trapped clone-27 (ART-27) is widely expressed in human tissues. Our previous studies showed that UXT regulates transcription repression including androgen receptor (AR) signaling in prostate cancer. Here we analyzed a tissue microarray consisting of normal prostate, benign prostatic hyperplasia, high grade prostatic intraepithelial neoplasia (HGPIN) and primary prostate cancer cases for UXT protein expression. We found that HGPIN and malignant tumors have significantly decreased UXT expression compared to the normal prostate. Loss of UXT expression in primary prostate cancer is positively associated with high Gleason grade and poor relapse-free survival. We engineered prostate-specific UxtKO mice that developed a hyperplastic phenotype with apparent prostate secretion fluid blockage as well as PIN by 4-6 months. Doubly mutant UxtKO/PtenKO mice developed a more aggressive PIN phenotype. UXT depletion in prostate cancer cells also increased retroelements expression, including LINE-1 and Alu. Consistent with this finding UxtKO mice have increased LINE-1 protein levels in the prostate compared to control mice. In addition, cancer cells with UXT depletion have increased retrotransposition activity and accumulated DNA damage. Our findings demonstrate that loss of UXT is an early event during prostate cancer progression, which may contribute to genome instability.

2'‑Hydroxyflavanone inhibits epithelial‑mesenchymal transition, and cell migration and invasion via suppression of the Wnt/β‑catenin signaling pathway in prostate cancer.

Despite the availability of a number of treatment options, certain cases of primary prostate cancer (PCa) will develop into metastatic PCa, in which epithelial‑mesenchymal transition (EMT) serves an important role. Recently, a natural flavonoid known as 2'‑hydroxyflavanone (2HF) exerts remarkable anticancer activity on various types of cancer. Our previous study demonstrated that 2HF could promote apoptosis and inhibit the proliferation of PCa cells, but whether 2HF is involved in the regulation of EMT, and cell migration and invasion in metastatic PCa remains unknown. The present study used two different metastatic PCa cell lines (PC‑3 and DU145) to investigate the effects of 2HF on EMT, and cell migration and invasion. The results demonstrated that 2HF could inhibit EMT, and cell migration and invasion through the Wnt/β‑catenin signaling pathway by suppressing GSK‑3β phosphorylation, β‑catenin expression and transactivation. In conclusion, the present study revealed a novel function of 2HF, which may be used to prevent or treat PCa metastasis.

Cancer/testis antigen SPATA19 is frequently expressed in benign prostatic hyperplasia and prostate cancer.

Spermatogenesis-associated 19 (SPATA19) is a cancer/testis antigen overexpressed in various cancers. However, its protein expression profile in malignant or non-malignant tissues remains unknown. Thus, in this study, we investigated SPATA19 protein expression patterns in a panel of non-malignant human samples and primary prostate cancer (PCa) with or without benign prostatic hyperplasia (BPH) tissues. SPATA19 was absent in all non-malignant tissues investigated (n=14) except testis and prostate tissues. In terms of malignancies, all PCa cases were positive for SPATA19 exhibiting frequency between 20 and 100% (median 85%) with 63 (52.5%) and 57 (47.5%) cases demonstrating weak/moderate and strong intensities, respectively. Thirty-nine PCa cases (32.5%) contained BPH, and all BPH glands were SPATA19 positive (frequency between 20 and 100%; median 90%) with 13 (33.3%) demonstrating strong SPATA19 expression. Higher SPATA19 expression (higher frequency, intensity, or H-score) was not associated with overall survival or disease-specific survival (DFS) in all PCa cases. However, biochemical recurrence (BR) was associated with worse DFS (p = 0.005) in this cohort of 120 patients, and cases with strong SPATA19 intensity were associated with BR (p = 0.020). In conclusion, we showed that SPATA19 protein was frequently expressed in both BPH and PCa glands, and this warrants future investigations on its pathogenic roles in the disease.

Abstract 4767: Generating and characterizing novel prostate cancer cell lines that employ the alternative lengthening of telomeres (ALT) telomere maintenance mechanism

Abstract A key hallmark of cancer is unlimited replication, which requires cancer cells to evade replicative senescence induced by telomere shortening. The majority of cancers overcome this critical barrier by up-regulating the enzyme telomerase, a telomere-specific reverse transcriptase. However, for a subset of cancers that lack telomerase, telomeres are maintained by employing the Alternative Lengthening of Telomeres (ALT) pathway, which is thought to be dependent on homologous recombination. In a variety of tumor types, our laboratory and others have reported a strong correlation between the ALT phenotype and recurrent cancer-associated somatic inactivating mutations ATRX or DAXX, genes encoding chromatin remodeling proteins. In a previous comprehensive survey of the ALT phenotype in cancer, we reported that the ALT phenotype is highly prevalent in some tumor types (e.g. astrocytoma, sarcomas, pancreatic neuroendocrine tumors), but we did not observe any ALT-positive cases in over 1,000 cases of primary prostate cancer. Notably, however, we found a subset of metastatic prostate cancer harbors the ALT phenotype, suggesting that mutations giving rise to ALT in this disease are unique to metastatic prostate cancer. Here, we have created the first prostate cancer cell lines exhibiting the ALT phenotype, with the purpose of molecularly characterizing ALT in prostate cancer and identifying promising therapeutic approaches for men with lethal metastatic prostate cancer harboring this phenotype. These novel cell lines were generated by inactivating ATRX using the CRISPR cas9 nickase system in a genetically well characterized prostate cancer cell line that normally expresses telomerase, as well as wild-type ATRX and DAXX. In this new model, abolishing ATRX expression is sufficient to induce the ALT phenotype, as assessed by multiple biomarkers of ALT, including bright telomeric FISH foci, ALT-associated PML bodies (ABPs), and c-circles. Interestingly, compared to the parental line, cells with compromised ATRX function have significantly lower telomerase activity and a five-fold decreased expression of telomerase reverse transcriptase (TERT). Ultimately, we will use these isogenic cell lines to further characterize and elucidate the basic biology of cancers harboring ALT, and pharmacologically target the molecular features unique to the ALT phenotype. The identification of ALT-specific drugs will pave the way for the development of new targeted treatments for a subset of men with lethal metastatic prostate cancer that harbor this unique molecular phenotype, and more broadly, other cancers that share the ALT phenotype in common. Citation Format: Mindy K. Graham, Jacqueline Brosnan-Cashman, Anthony Rizzo, Michael Haffner, Alan Meeker, Christopher Heaphy. Generating and characterizing novel prostate cancer cell lines that employ the alternative lengthening of telomeres (ALT) telomere maintenance mechanism. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4767.

Characteristics of cases with unknown stage prostate cancer in a population-based cancer registry

BackgroundThe New South Wales Central Cancer Registry (NSW CCR) is the only population-based cancer registry in Australia that has routinely collected summary stage at diagnosis since its inception in 1972. However, a large proportion of prostate cancer cases have “unknown” stage recorded by the registry. We investigated the characteristics of prostate cancer cases with “unknown” stage recorded by the NSW CCR, and examined survival for this group. MethodsData were obtained from the NSW CCR for all first primary prostate cancer cases diagnosed in 1999–2007. Summary stage was recorded as localised, regional, distant or “unknown”. Associations between disease stage and patient characteristics (age, place of residence at diagnosis, year of diagnosis and country of birth) and prostate cancer specific survival were investigated using multivariable logistic regression and Cox proportional hazards models respectively. ResultsOf 39852 prostate cancer cases, 41.8% had “unknown” stage recorded by the NSW CCR. This proportion decreased significantly over time, increased with increasing age at diagnosis and was higher for those living in socio-economically disadvantaged areas. The proportion with “unknown” stage varied across area health services. Prostate cancer specific survival for cases with “unknown” stage was significantly poorer than for those with localised stage but better than for those with regional or distant stage. ConclusionsResearchers or others using cancer registry stage data to examine prostate cancer outcomes need to consider the differences between cases with “unknown” stage at diagnosis and those with known stage recorded by the registry, and what impact this may have on their results.

L-type amino acid transporter 1 expression is highly correlated with Gleason score in prostate cancer

Upregulation of L-type amino acid transporter 1 (LAT1), a member of the system L amino acid transporter family, may be detected by immunohistochemical methods. Immunoreactive LAT1 expression in prostate cancer is considered to be a promising biomarker for high-grade malignancy. However, the mutual association between LAT1 and Gleason score, the most fixed indicator for grading the malignancy of prostate cancers, remains to be elucidated. The aim of this study was to clarify the correlations between LAT1 and other factors in prostate cancer, including the Gleason score. We evaluated 54 cases of primary prostate cancer, surgically resected without any neoadjuvant therapies and performed immunohistochemistry for LAT1, Ki-67, CD34 and vascular endothelial growth factor on the tissue sections. The Gleason score as well as the age, pathological stage (pStage) of prostate cancer and serum concentration of prostate-specific antigen (PSA) of each case were also assessed. Statistical analysis for the correlations between LAT1 expression and Gleason score and each of the other characteristics studied was performed. As a result, a strong significant correlation between immuno-reactive LAT1 expression and Gleason score was identified (P<0.01). We concluded that immunoreactive LAT1 expression in tissue sections of prostate cancer may be useful as a biomarker for high-grade malignancy.

Folate intake, alcohol consumption, and the methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism: influence on prostate cancer risk and interactions

Purpose: Folate is essential to DNA methylation and synthesis and may have a complex dualistic role in prostate cancer. Alcohol use may increase risk and epigenetic factors may interact with lifestyle exposures. We aimed to characterize the independent and joint effects of folate intake, alcohol consumption, and the MTHFR C677T gene polymorphism on prostate cancer risk, while accounting for intakes of vitamins B2, B6, B12, methionine, total energy, and confounders. Methods: A case-control study was conducted at Kingston General Hospital of 80 incident primary prostate cancer cases and 334 urology clinic controls, all with normal age-specific PSA levels (to exclude latent prostate cancers). Participants completed a questionnaire on folate and alcohol intakes and potential confounders prior to knowledge of diagnosis, eliminating recall bias, and blood was drawn for MTHFR genotyping. Joint effects of exposures were assessed using unconditional logistic regression and significance of multiplicative and additive interactions using general linear models. Results: Folate, vitamins B2, B6, B12, methionine, and the CT and TT genotypes were not associated with prostate cancer risk. The highest tertile of lifetime alcohol consumption was associated with increased risk (OR = 2.08; 95% CI: 1.12–3.86). Consumption of >5 alcoholic drinks per week was associated with increased prostate cancer risk among men with low folate intake (OR = 2.38; 95% CI: 1.01–5.57), and higher risk among those with the CC MTHFR genotype (OR = 4.43; 95% CI: 1.15–17.05). Increased risk was also apparent for average weekly alcohol consumption when accounting for the multiplicative interaction between folate intake and MTHFR C677T genotype (OR = 3.22; 95% CI: 1.36–7.59). Conclusion: Alcohol consumption is associated with increased prostate cancer risk, and this association is stronger among men with low folate intake, with the CC MTHFR genotype, and when accounting for the joint effect of folate intake and MTHFR C677T genotype.

Prostatakarzinomzentren und Hodentumorzweitmeinungszentren

Establishment of organ site-specific cancer centers by the German Cancer Society (GCS) is part of the basic politically driven reform of oncology care in Germany. Since 2007 an increasing number of prostate cancer centers have been guided toward certification by the OnkoZert GmbH of the GCS. Currently 68 centers are certified and together with ongoing certification proceedings will amount to 81 prostate cancer centers, which cover about one fourth of cases of primary prostate cancer. Urology is of particular importance in the management of these centers. For the most part, urologists belonging to a clinical unit are the initiators of the certification process, thus ensuring that uro-oncology is firmly entrenched in the specialty with involvement of outpatient service providers. Fears that authority will be lost are unfounded as long as responsibility for this task is taken seriously and active use is made of the possibilities for creativity. A similarly important function is fulfilled by the testicular cancer centers that offer second opinion services, which were initiated by urology conjointly with German Cancer Aid to pursue the goal of quality assurance for this tumor entity and therefore likewise secure the position of this tumor in the realm of urologists. By applying such strategic approaches, urologists will succeed in sustainably safeguarding their future importance in a very competitive environment and in counteracting the encroachments of other specialties by exhibiting clear orientation.

555 PTEN GENE MUTATION AND PRIMARY PROSTATE CANCER PROGRESSION

You have accessJournal of UrologyProstate Cancer: Basic Research IV1 Apr 2010555 PTEN GENE MUTATION AND PRIMARY PROSTATE CANCER PROGRESSION Sepehr Salem, Abdolrasoul Mehrsai, Amirreza Abedi, Maedeh Rezaeidanesh, and Golamreza Pourmand Sepehr SalemSepehr Salem More articles by this author , Abdolrasoul MehrsaiAbdolrasoul Mehrsai More articles by this author , Amirreza AbediAmirreza Abedi More articles by this author , Maedeh RezaeidaneshMaedeh Rezaeidanesh More articles by this author , and Golamreza PourmandGolamreza Pourmand More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.775AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail 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 (PCR-SSCP 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 prostate-specific 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. Tehran, Iran© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e218 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Sepehr Salem More articles by this author Abdolrasoul Mehrsai More articles by this author Amirreza Abedi More articles by this author Maedeh Rezaeidanesh More articles by this author Golamreza Pourmand More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

The androgen‐regulated type II serine protease TMPRSS2 is differentially expressed and mislocalized in prostate adenocarcinoma

Transmembrane serine protease 2 (TMPRSS2) is an androgen-regulated member of the type two transmembrane protease (TTSP) family. Two other members of the TTSP family, matriptase and hepsin, are over-expressed in prostate adenocarcinoma and mechanistically influence cancer cell invasion and metastasis. This study was performed to determine TMPRSS2 protein expression in primary and metastatic prostate cancers. We developed a monoclonal antibody capable of the sensitive and specific detection of TMPRSS2 protein. TMPRSS2 regulation by androgen and presence in seminal fluid was measured. TMPRSS2 localization and expression was evaluated in 415 cases of primary prostate cancer and 144 prostate cancer metastases by immunohistochemistry. We determined that TMPRSS2 protein expression is regulated by androgens and that TMPRSS2 is a component of the normal seminal fluid proteome. TMPRSS2 protein is abundantly expressed in the prostate, with low levels in the epithelia of the colon, stomach, epididymis and breast. Pancreatic acini, hepatic bile ducts, testicular Leydig cells and the kidney also express TMPRSS2. In the prostate, TMPRSS2 protein is specifically localized to the secretory epithelium, with enhanced expression in the plasma membrane orientated towards the ductal lumen. TMPRSS2 expression was significantly higher in both neoplastic prostate and in the epithelium of prostatic hyperplasia compared to normal epithelium (p < 0.01). TMPRSS2 expression was further elevated in higher Gleason grade cancers (patterns 4 and 5) compared to pattern 3 (p = 0.04). Furthermore, in most high-grade cancers, TMPRSS2 was mislocalized, being expressed in the cytoplasm as well as in the cell membrane. Prostate cancer metastases also generally expressed high levels of TMPRSS2. In summary, the TMPRSS2 protease is expressed highly in primary and metastatic prostate cancers and is associated with tumour cell differentiation. Based on studies with the related proteins matriptase and hepsin, TMPRSS2 should be investigated for causal roles in prostate carcinogenesis.

Identification and Characterization of Novel Spliced Variants of Neuregulin 4 in Prostate Cancer

The neuregulin (NRG) 1, 2, and 3 genes undergo extensive alternative mRNA splicing, which results in variants that show structural and functional diversity. The aims of this study were to establish whether the fourth member of this family, NRG4, is expressed in prostate cancer, if it is alternatively spliced and whether any functional differences between the variants could be observed. The expression of NRG4 was determined using immunohistochemical staining of 40 cases of primary prostate cancer. Bioinformatic analysis and reverse transcription-PCR (RT-PCR) using NRG4 isotype-specific primers on a panel of normal and prostate cancer cell lines were used to identify alternatively spliced NRG4 variants. Expression of these variants was determined using isotype-specific antibodies. Transfection into Cos-7 cells of two of these green fluorescent protein-tagged variants allowed analysis of their subcellular location. Four of the variants were chemically synthesized and tested for their ability to activate the ErbB4 receptor. NRG4 was variably expressed in the cytoplasm in the majority of prostate cancer cases, and in a subset of cases in the membrane, high levels were associated with advanced disease stage. Four novel NRG4 splice variants (NRGA2, NRG4 B1-3) were characterized, where each seemed to have a different subcellular location and were also expressed in the cytoplasm of the prostate tumors. NRG4 B3 was also present in endothelial cells. In transfected cells, the A type variant (NRG4 A1) was localized to the membrane, whereas the B type variant (NRG4 B1), which lacks the predicted transmembrane region, had an intracellular localization. Only the variants with an intact epidermal growth factor-like domain activated ErbB4 signaling. NRG4 overexpression is associated with advanced-stage prostate cancer. The alternative splice variants may have different roles in cell signaling, some acting as classic receptor ligands and some with as-yet unknown functions.

Genetic variation in interleukin 8 and its receptor genes and its influence on the risk and prognosis of prostate cancer among Finnish men in a large cancer prevention trial

The cytokine interleukin 8 (IL-8) may play a role in the pathogenesis of prostate cancer through the modulation of tumour immune response or enhanced angiogenesis. A common polymorphism of the IL-8 (-251) gene, which may affect the production level of the cytokine, has been inversely associated with a number of diseases, including prostate cancer. We examined the most representative single nucleotide polymorphisms (SNPs) for the IL-8 and its receptors (CXCR1 and CXCR2) genes, and conducted a case-control study nested within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study to examine if these SNPs are associated with susceptibility to and prognosis of prostate cancer. Using incidence density sampling, 584 cases of primary prostate cancer and 584 matched controls were selected. In this population, we observed no strong association between the SNPs for IL-8 -251 (A-->T), CXCR1 +860 (C-->G) and CXCR2 -1010 (A-->G) and either the subsequent risk of prostate cancer or individual prognostic factors among cases. Although none of the SNPs studied are likely to have major effects on prostate cancer susceptibility, a role for other polymorphisms associated within these genes cannot be excluded.