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Arsenite-resistance protein 2, also known as serrate RNA effector molecule (ARS2/SRRT), is known to be involved in cellular proliferation and tumorigenicity. However, its role in prostate cancer (PCa) has not yet been established. We investigated the potential role of SRRT in 496 prostate samples including benign, incidental, advanced, and castrate-resistant patients treated by androgen deprivation therapy (ADT). We also explored the association of SRRT with common genetic aberrations in lethal PCa using immunohistochemistry (IHC) and performed a detailed analysis of SRRT expression using The Cancer Genome Atlas (TCGA PRAD) by utilizing RNA-seq, clinical information (pathological T category and pathological Gleason score). Our findings indicated that high SRRT expression was significantly associated with poor overall survival (OS) and cause-specific survival (CSS). SRRT expression was also significantly associated with common genomic aberrations in lethal PCa such as PTEN loss, ERG gain, mutant TP53, or ATM. Furthermore, TCGA PRAD data revealed that high SRRT mRNA expression was significantly associated with higher Gleason scores, PSA levels, and T pathological categories. Gene set enrichment analysis (GSEA) of RNAseq data from the TCGA PRAD cohort indicated that SRRT may play a potential role in regulating the expression of genes involved in prostate cancer aggressiveness. Conclusion: The current data identify the SRRTs potential role as a prognostic for lethal PCa, and further research is required to investigate its potential as a therapeutic target.

BackgroundAtaxia Telangiectasia Mutated (ATM) serine/threonine protein kinase is a known tumor suppressor, involved in DNA damage repair. It has prognostic and predictive therapeutic implications and is associated with aggressive prostate cancer (PCa).ObjectiveTo investigate the prognostic value of ATM protein expression in PCa patients and assessed the combined value of ATM, ERG, and PTEN status.Design setting and participantsThis study consisted of 303 patients with incidental, locally advanced, and castrate-resistant PCa by transurethral resection of the prostate (TURP).Outcome measurements and statistical analysisTURP samples from 303 PCa patients were assessed by immunohistochemistry (IHC for ATM, ERG, and PTEN. Individual and combined marker status were correlated with International Society of Urological Pathology Gleason grade group, overall survival (OS), and PCa-specific mortality (PCSM).Results and limitationsDecreased ATM expression (negative/weak intensity) occurred in 164/303 (54.1%) patients, and was associated with shorter OS and higher PCSM (p = 0.015 and p = 0.001, respectively). Negative/weak ATM expression was significantly associated with PCSM with a hazard ratio of 2.09 (95% confidence interval 1.34-3.27, p = 0.001). Assessment of Combined ATM/PTEN expression showed improved prognostic power to predict OS and PCSM, independent of Gleason grade groups.ConclusionsDecreased ATM protein expression is associated with poor outcomes in advanced PCa patients. Patients with combined low ATM/PTEN negative expression are at the highest risk for reduced OS and PCSM. Assessing the combined status of ATM/PTEN by IHC in PCa patients may aid in risk stratification relative to OS and PCSM. Moreover, since ATM plays an integral role in DNA damage response pathways, future studies will enhance our understanding of how outcomes of patients with altered ATM and PTEN expression can be improved further with poly-ADP ribose polymerase inhibitors (PARPi), combinations of PARPi and androgen receptor-targeted therapies, as well as platinum-based chemotherapies.Patient summaryLower ATM intensity is associated with increased cancer-specific mortality in prostate cancer patients. Patients with lower ATM and PTEN negative expression showed decreased overall survival and increased cancer mortality compared with controls.

Our knowledge of prostate cancer (PCa) genomics mainly reflects European (EUR) and Asian (ASN) populations. Our understanding of the influence of Middle Eastern (ME) and African (AFR) ancestry on the mutational profiles of prostate cancer is limited. To characterize genomic differences between ME, EUR, ASN, and AFR ancestry, fluorescent in situ hybridization (FISH) studies for NKX3-1 deletion and MYC amplification were carried out on 42 tumors arising in individuals of ME ancestry. These were supplemented by analysis of genome-wide copy number profiles of 401 tumors of all ancestries. FISH results of NKX3-1 and MYC were assessed in the ME cohort and compared to other ancestries. Gene level copy number aberrations (CNAs) for each sample were statistically compared between ancestry groups. NKX3-1 deletions by FISH were observed in 17/42 (17.5%) prostate tumors arising in men of ME ancestry, while MYC amplifications were only observed in 1/42 (2.3%). Using CNAs called from arrays, the incidence of NKX3-1 deletions was significantly lower in ME vs. other ancestries (20% vs. 52%; p = 2.3 × 10-3). Across the genome, tumors arising in men of ME ancestry had fewer CNAs than those in men of other ancestries (p = 0.014). Additionally, the somatic amplification of 21 specific genes was more frequent in tumors arising in men of ME vs. EUR ancestry (two-sided proportion test; Q < 0.05). Those included amplifications in the glutathione S-transferase family on chromosome 1 (GSTM1, GSTM2, GSTM5) and the IQ motif-containing family on chromosome 3 (IQCF1, IQCF2, IQCF13, IQCF4, IQCF5, IQCF6). Larger studies investigating ME populations are warranted to confirm these observations.

BackgroundWe aimed to validate Decipher to predict adverse pathology (AP) at radical prostatectomy (RP) in men with National Comprehensive Cancer Network (NCCN) favorable-intermediate risk (F-IR) prostate cancer (PCa), and to better select F-IR candidates for active surveillance (AS).MethodsIn all, 647 patients diagnosed with NCCN very low/low risk (VL/LR) or F-IR prostate cancer were identified from a multi-institutional PCa biopsy database; all underwent RP with complete postoperative clinicopathological information and Decipher genomic risk scores. The performance of all risk assessment tools was evaluated using logistic regression model for the endpoint of AP, defined as grade group 3-5, pT3b or higher, or lymph node invasion.ResultsThe median age was 61 years (interquartile range 56-66) for 220 patients with NCCN F-IR disease, 53% classified as low-risk by Cancer of the Prostate Risk Assessment (CAPRA 0-2) and 47% as intermediate-risk (CAPRA 3-5). Decipher classified 79%, 13% and 8% of men as low-, intermediate- and high-risk with 13%, 10%, and 41% rate of AP, respectively. Decipher was an independent predictor of AP with an odds ratio of 1.34 per 0.1 unit increased (p value = 0.002) and remained significant when adjusting by CAPRA. Notably, F-IR with Decipher low or intermediate score did not associate with significantly higher odds of AP compared to VL/LR.ConclusionsNCCN risk groups, including F-IR, are highly heterogeneous and should be replaced with multivariable risk-stratification. In particular, incorporating Decipher may be useful for safely expanding the use of AS in this patient population.

Circulating insulin-like growth factor-1 (IGF-1) is consistently associated with prostate cancer risk. IGF-1 binds to IGF-1 receptor (IGF1R) and insulin receptor (IR), activating cancer hallmark pathways. Experimental evidence suggests that TMPRSS2:ERG may interact with IGF/insulin signaling to influence progression. We investigated IGF1R and IR expression and its association with lethal prostate cancer among 769 men. Protein expression of IGF1R, IR and ERG (i.e. a surrogate of ERG fusion genes) were assayed by immunohistochemistry. Cox models estimated hazard ratios (HR) and 95% confidence intervals (CI) adjusted for clinical characteristics. Among patients, 29% had strong tumor IGF1R expression and 10% had strong IR expression. During a mean follow-up of 13.2 years through 2012, 80 men (11%) developed lethal disease. Tumors with strong IGF1R or IR expression showed increased cell proliferation, decreased apoptosis and a higher prevalence of ERG. In multivariable models, strong IGF1R was associated with a borderline increased risk of lethal prostate cancer (HR 1.7; 95% CI 0.9-3.1). The association appeared greater in ERG-positive tumors (HR 2.8; 95% CI 0.9-8.4) than in ERG-negative tumors (HR 1.3; 95% CI 0.6-3.0, p-heterogeneity 0.08). There was no association between IR and lethal prostate cancer (HR 0.8; 95% CI 0.4-1.9). These results suggest that tumor IGF1R expression may play a role in prostate cancer progression to a lethal phenotype and that ERG-positive tumors may be more sensitive to IGF signaling. These data may improve our understanding of IGF signaling in prostate cancer and suggest therapeutic options for disease subtypes.

Late endosomal/lysosomal adaptor, MAPK and mTOR, or LAMTOR, is a scaffold protein complex that senses nutrients and integrates growth factor signaling. The role of LAMTOR4 in tumorigenesis is still unknown. However, there is a considerable possibility that LAMTOR4 is directly involved in tumor cell proliferation and metastasis. In the current study, we investigated the protein expression of LAMTOR4 in a cohort of 314 men who were undergoing transurethral resection of prostate (TURP) consisting of incidental, advanced and castration-resistant cases. We also correlated the data with ERG and PTEN genomic status and clinicopathological features including Gleason score and patients' outcome. Additionally, we performed in vitro experiments utilizing knockdown of LAMTOR4 in prostate cell lines, and we performed mRNA expression assessment using TCGA prostate adenocarcinoma (TCGA-PRAD) to explore the potential differentially expressed genes and pathways associated with LAMTOR4 overexpression in PCa patients. Our data indicate that high LAMTOR4 protein expression was significantly associated with poor overall survival (OS) (HR: 1.44, CI: 1.01–2.05, p = 0.047) and unfavorable cause-specific survival (CSS) (HR: 1.71, CI: 1.06–2.77, p = 0.028). Additionally, when high LAMTOR4 expression was combined with PTEN-negative cases (score 0), we found significantly poorer OS (HR: 2.22, CI: 1.37–3.59, p = 0.001) and CSS (HR: 3.46, CI: 1.86–6.46, p < 0.0001). Furthermore, ERG-positive cases with high LAMTOR4 exhibited lower OS (HR: 1.98, CI: 1.18–3.31, p = 0.01) and CSS (HR: 2.54, CI: 1.32–4.87, p = 0.005). In vitro assessment showed that knockdown of LAMTOR4 decreases PCa cell proliferation, migration, and invasion. Our data further showed that knockdown of LAMTOR4 in the LNCaP cell line significantly dysregulated the β catenin/mTOR pathway and tumorigenesis associated pathways. Inhibiting components of the mTOR pathway, including LAMTOR4, might offer a strategy to inhibit tumor progression and metastasis in prostate cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: SETD2, a histone methyltransferase and epigenetic modifier, and SETD2 protein expression were explored in a prostate cancer non-surgical cohort of 202 cases. Notably, SETD2 showed higher intensity in advanced and castrate-resistant disease compared to incidental cases. Moreover, elevated SETD2 expression is significantly associated with poorer prognosis, lower overall survival (OS), and decreased cancer-specific survival (CSS). High-risk SETD2 combined with PTEN loss or ERG positivity improved the prognostication for these outcomes. Additionally, the TCPA protein database and TCGA PRAD GSEA implicated SETD2 in pathways linked to tumor progression, chemoresistance, and adverse prognosis, including the AMPK, cAMP, and PI3K-Akt signaling pathways. SET-domain containing 2 (SETD2) is a histone methyltransferase and an epigenetic modifier with oncogenic functionality. In the current study, we investigated the potential prognostic role of SETD2 in prostate cancer. A cohort of 202 patients' samples was assembled on tissue microarrays (TMAs) containing incidental, advanced, and castrate-resistant CRPCa cases. Our data showed significant elevated SETD2 expression in advanced and castrate-resistant disease (CRPCa) compared to incidental cases (2.53 ± 0.58 and 2.21 ± 0.63 vs. 1.9 ± 0.68; p < 0.001, respectively). Interestingly, the mean intensity of SETD2 expression in deceased vs. alive patients was also significantly different (2.31 ± 0.66 vs. 2 ± 0.68; p = 0.003, respectively). Overall, high SETD2 expression was found to be considered high risk and was significantly associated with poor prognosis and worse overall survival (OS) (HR 1.80; 95% CI: 1.28–2.53, p = 0.001) and lower cause specific survival (CSS) (HR 3.14; 95% CI: 1.94–5.08, p < 0.0001). Moreover, combining high-intensity SETD2 with PTEN loss resulted in lower OS (HR 2.12; 95% CI: 1.22–3.69, p = 0.008) and unfavorable CSS (HR 3.74; 95% CI: 1.67–8.34, p = 0.001). Additionally, high SETD2 intensity with ERG positive expression showed worse prognosis for both OS (HR 1.99, 95% CI 0.87–4.59; p = 0.015) and CSS (HR 2.14, 95% CI 0.98–4.68, p = 0.058). We also investigated the protein expression database TCPA, and our results showed that high SETD2 expression is associated with a poor prognosis. Finally, we performed TCGA PRAD gene set enrichment analysis (GSEA) data for SETD2 overexpression, and our data revealed a potential association with pathways involved in tumor progression such as the AMPK signaling pathway, the cAMP signaling pathway, and the PI3K-Akt signaling pathway, which are potentially associated with tumor progression, chemoresistance, and a poor prognosis. [ABSTRACT FROM AUTHOR]

A complete proteomics study characterizing active androgen receptor (AR) complexes in prostate cancer (PCa) cells identified a diversity of protein interactors with tumorigenic annotations, including known RNA splicing factors. Thus, we chose to further investigate the functional role of AR-mediated alternative RNA splicing in PCa disease progression. We selected two AR-interacting RNA splicing factors, Src associated in mitosis of 68 kDa (SAM68) and DEAD (Asp-Glu-Ala-Asp) box helicase 5 (DDX5) to examine their associative roles in AR-dependent alternative RNA splicing. To assess the true physiological role of AR in alternative RNA splicing, we assessed splicing profiles of LNCaP PCa cells using exon microarrays and correlated the results to PCa clinical datasets. As a result, we were able to highlight alternative splicing events of clinical significance. Initial use of exon-mini gene cassettes illustrated hormone-dependent AR-mediated exon-inclusion splicing events with SAM68 or exon-exclusion splicing events with DDX5 overexpression. The physiological significance in PCa was investigated through the application of clinical exon array analysis, where we identified exon-gene sets that were able to delineate aggressive disease progression profiles and predict patient disease-free outcomes independently of pathological clinical criteria. Using a clinical dataset with patients categorized as prostate cancer-specific death (PCSD), these exon gene sets further identified a select group of patients with extremely poor disease-free outcomes. Overall, these results strongly suggest a nonclassical role of AR in mediating robust alternative RNA splicing in PCa. Moreover, AR-mediated alternative spicing contributes to aggressive PCa progression, where we identified a new subtype of lethal PCa defined by AR-dependent alternative splicing. [ABSTRACT FROM AUTHOR]

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* Background and Objective.--Hemorrhagic endovasculitis (HEV) is a vasodisruptive alteration of fetal-placental blood vessels that has been associated with perinatal morbidity and mortality and abnormalities of growth and development. Clinicopathologic conditions that are often identified in pregnancies with HEV-affected placentas include villitis of unknown etiology, chorionic vessel thrombi, villous erythroblastosis, meconium staining, and maternal hypertension. The clinical implications of HEV are often disputed. This case-control study assesses the clinical relevance of HEV in placentas of viable infants and examines the interplay of coexistent intraplacental lesions. Methods.--We reviewed clinical records and slides from 104 livebirths with placentas affected by HEV above a specified severity level (cases) and 104 matched live-births with placentas that were not affected by HEV (controls). We evaluated incidences of perinatal complications with increasing HEV severity indices in placentas with and without coexistent lesions. Interlesional relationships were established by matching HEV severity indices with severity indices of coexistent lesions. Hemorrhagic endovasculitis was subcategorized into active, bland, and healed forms and clustered capillary lesions (hemorrhagic villitis). Results.--Lesions that were frequently coexistent in HEV-affected placentas included villitis of unknown etiology, chorionic thrombi, villous fibrosis, erythroblastosis, and primary infarcts. Compared with the control group, the case group had higher incidences of abnormal fetal heart rate tracings (P < .003), fetal distress (P < .001), and growth restriction (P < .001). Increasing severities of HEV and coexistent lesions were associated with higher rates of perinatal complications. Complication rates were higher in HEV cases, with or without coexistent lesions. The complication rate was higher in cases affected by HEV and hemorrhagic villitis than in cases affected by HEV alone (P < .03). Significant interlesional relationships were evident between HEV and villitis of unknown etiology, chorionic thrombi, villous fibrosis, and erythroblastosis. Conclusions.--Severe forms of HEV can occur in placentas of livebirths. The severity of HEV and associated lesions and the presence of hemorrhagic villitis have important clinical implications. Interlesional relationships between HEV and thrombotic, chronic inflammatory, and chronic vaso-occlusive lesions exist. Pregnancies with HEV-affected placentas with or without coexistent lesions are at risk for perinatal complications., Hemorrhagic endovasculitis (HEV) is a vasodisruptive alteration of fetal-placental blood vessels first described in 1980. (1) Studies carried out in subsequent years have shown associations between this lesion and stillbirth, [...]

Context.--Diagnostic use of immunohistochemistry has been extensively studied in prostate needle biopsy, but its use in routine practice and the quality assurance and associated cost have not been previously addressed. Objective.--To examine the routine use of immunohistochemistry in prostate biopsies in a tertiary academic institution. Design.--We reviewed reports of 748 consecutive prostate biopsies and we evaluated the turnaround times, the final diagnosis on individual specimens, the intradepartmental consultation rates, and the associated costs. Results.--Immunohistochemistry evaluation was required for 39.4% of biopsies and 12% of blocks (average 1.8 blocks/case). The biopsies with immunohistochemistry were signed out 1.7 workdays later (8.6 versus 6.9 days). The diagnostic breakdown for individual blocks evaluated by immunohistochemistry was Cancer 47.7%; Atypical, Suspicious 10.8%; Small Atypical Glands Adjacent to High-Grade Prostatic Intraepithelial Neoplasia 6.9%; High-Grade Prostatic Intraepithelial Neoplasia 12.4%; and Benign 22.2%. Diagnoses of Cancer or Atypical, Suspicious (Atypical, Suspicious + Small Atypical Glands Adjacent to High-Grade Prostatic Intraepithelial Neoplasia) were rendered in 65.4% of individual blocks assessed by immunohistochemistry. Immunohistochemistry aided in establishing limited cancer ([less than or equal to] 10% of core) in 69.3% of cases and in 74% of single-core-positive biopsies. Departmental consultation was performed in 18.3% of biopsies and immunohistochemistry was used in 68% of these cases. Both immunohistochemistry and consultation were performed in 55.8% of Atypical, Suspicious cases. The average immunohistochemistry cost per biopsy was $22.34 and the estimated annual cost for prostate biopsy immunohistochemistry in our laboratory was $33 420.64. Conclusions.--Immunohistochemistry is frequently used in our prostate biopsy practice to establish or confirm a limited Cancer diagnosis, to better resolve diagnostic ambiguity, or for quality assurance. The data provided herein can be used for comparisons with other prostate biopsy practices. (Arch Pathol Lab Med. 2013;137:541-545; doi: 10.5858/arpa.2012-0145-OA), Immunohistochemistry (IHC) has substantially altered the practice of surgical pathology and cytopathology in the past 2 decades, but the use of IHC has particularly increased in cancer-related pathology. The use [...]