Molecular profiling of ETS and non-ETS aberrations in prostate cancer patients from northern India

Prostate. 2015 Mar 23.

Ateeq B, Kunju LP, Carskadon SL, Pandey SK, Singh G, Pradeep I, Tandon V, Singhai A, Goel A, Amit S, Agarwal A, Dinda AK, Seth A, Tsodikov A, Chinnaiyan AM, Palanisamy N.
PMID: 25809148 | DOI: 10.1002/pros.22989.

BACKGROUND: Molecular stratification of prostate cancer (PCa) based on genetic aberrations including ETS or RAF gene-rearrangements, PTEN deletion, and SPINK1 over-expression show clear prognostic and diagnostic utility. Gene rearrangements involving ETS transcription factors are frequent pathogenetic somatic events observed in PCa. Incidence of ETS rearrangements in Caucasian PCa patients has been reported, however, occurrence in Indian population is largely unknown. The aim of this study was to determine the prevalence of the ETS and RAF kinase gene rearrangements, SPINK1 over-expression, and PTEN deletion in this cohort. METHODS: In this multi-center study, formalin-fixed paraffin embedded (FFPE) PCa specimens (n = 121) were procured from four major medical institutions in India. The tissues were sectioned and molecular profiling was done using immunohistochemistry (IHC), RNA in situ hybridization (RNA-ISH) and/or fluorescence in situ hybridization (FISH). RESULTS: ERG over-expression was detected in 48.9% (46/94) PCa specimens by IHC, which was confirmed in a subset of cases by FISH. Among other ETS family members, while ETV1 transcript was detected in one case by RNA-ISH, no alteration in ETV4 was observed. SPINK1 over-expression was observed in 12.5% (12/96) and PTEN deletion in 21.52% (17/79) of the total PCa cases. Interestingly, PTEN deletion was found in 30% of the ERG-positive cases (P = 0.017) but in only one case with SPINK1 over-expression (P = 0.67). BRAF and RAF1 gene rearrangements were detected in ∼1% and ∼4.5% of the PCa cases, respectively. CONCLUSIONS: This is the first report on comprehensive molecular profiling of the major spectrum of the causal aberrations in Indian men with PCa. Our findings suggest that ETS gene rearrangement and SPINK1 over-expression patterns in North Indian population largely resembled those observed in Caucasian population but differed from Japanese and Chinese PCa patients. The molecular profiling data presented in this study could help in clinical decision-making for the pursuit of surgery, diagnosis, and in selection of therapeutic intervention. Prostate © 2015 The Authors. The Prostate, published by Wiley Periodicals, Inc.

Novel RNA Hybridization Method for the In Situ Detection of ETV1, ETV4, and ETV5 Gene Fusions in Prostate Cancer.

Appl Immunohistochem Mol Morphol. 2014 Sep;22(8):e32-40.

Kunju LP, Carskadon S, Siddiqui J, Tomlins SA, Chinnaiyan AM, Palanisamy N.
PMID: 25203299 | DOI: 10.1097/PAI.0000000000000095.

The genetic basis of 50% to 60% of prostate cancer (PCa) is attributable to rearrangements in E26 transformation-specific (ETS) (ERG, ETV1, ETV4, and ETV5), BRAF, and RAF1 genes and overexpression of SPINK1. The development and validation of reliable detection methods are warranted to classify various molecular subtypes of PCa for diagnostic and prognostic purposes. ETS gene rearrangements are typically detected by fluorescence in situ hybridization and reverse-transcription polymerase chain reaction methods. Recently, monoclonal antibodies against ERG have been developed that detect the truncated ERG protein in immunohistochemical assays where staining levels are strongly correlated with ERG rearrangement status by fluorescence in situ hybridization. However, specific antibodies for ETV1, ETV4, and ETV5 are unavailable, challenging their clinical use. We developed a novel RNA in situ hybridization-based assay for the in situ detection of ETV1, ETV4, and ETV5 in formalin-fixed paraffin-embedded tissues from prostate needle biopsies, prostatectomy, and metastatic PCa specimens using RNA probes. Further, with combined RNA in situ hybridization and immunohistochemistry we identified a rare subset of PCa with dual ETS gene rearrangements in collisions of independent tumor foci. The high specificity and sensitivity of RNA in situ hybridization provides an alternate method enabling bright-field in situ detection of ETS gene aberrations in routine clinically available PCa specimens.

Analytic Validation of RNA In Situ Hybridization (RISH) for AR and AR-V7 Expression in Human Prostate Cancer.

Clin Cancer Res.

2016 May 10

Guedes L, Morais C, Almutairi F, Haffner MC, Zheng Q, Isaacs JT, Antonarakis ES, Lu C, Tsai H, Luo J, De Marzo AM, Lotan TL.
PMID: 27166397 | DOI: -

Abstract

PURPOSE:

RNA expression of androgen receptor splice variants may be a biomarker of resistance to novel androgen deprivation therapies in castrate resistant prostate cancer (CRPC). We analytically validated an RNA in situ hybridization (RISH) assay for total AR and AR-V7 for use in formalin fixed paraffin embedded (FFPE) prostate tumors.

EXPERIMENTAL DESIGN:

We used prostate cell lines and xenografts to validate chromogenic RISH to detect RNA containing AR exon 1 (AR-E1, surrogate for total AR RNA species) and cryptic exon 3 (AR-CE3, surrogate for AR-V7 expression). RISH signals were quantified in FFPE primary tumors and CRPC specimens, comparing to known AR and AR-V7 status by immunohistochemistry and RT-PCR.

RESULTS:

The quantified RISH results correlated significantly with total AR and AR-V7 levels by RT-PCR in cell lines, xenografts and autopsy metastases. Both AR-E1 and AR-CE3 RISH signals were localized in nuclear punctae in addition to the expected cytoplasmic speckles. Compared to admixed benign glands, AR-E1 expression was significantly higher in primary tumor cells with a median fold increase of 3.0 and 1.4 in two independent cohorts (p<0.0001 and p=0.04, respectively). While AR-CE3 expression was detectable in primary prostatic tumors, levels were substantially higher in a subset of CRPC metastases and cell lines, and were correlated with AR-E1 expression.

CONCLUSIONS:

RISH for AR-E1 and AR-CE3 is an analytically valid method to examine total AR and AR-V7 RNA levels in FFPE tissues. Future clinical validation studies are required to determine whether AR RISH is a prognostic or predictive biomarker in specific clinical contexts.

ETV1 mRNA is specifically expressed in gastrointestinal stromal tumors

Virchows Arch. 2015 Aug 5.

Jang BG, Lee HE, Kim WH.
PMID: 26243012

Gastrointestinal stromal tumors (GISTs) develop from interstitial cells of Cajal (ICCs) mainly by activating mutations in the KIT or PDGFRA genes. Immunohistochemical analysis for KIT, DOG1, and PKC-θ is used for the diagnosis of GIST. Recently, ETV1 has been shown to be a lineage survival factor for ICCs and required for tumorigenesis of GIST. We investigated the diagnostic value of ETV1expression in GIST. On fresh-frozen tissue samples, RT-PCR analysis showed that ETV1 as well as KIT, DOG1, and PKC-θ are highly expressed in GISTs. On tissue microarrays containing 407 GISTs and 120 non-GIST mesenchymal tumors of GI tract, we performed RNA in situ hybridization (ISH) for ETV1 together with immunohistochemical analysis for KIT, DOG1, PKC-θ, CD133, and CD44. Overall, 387 (95 %) of GISTs were positive for ETV1, while KIT and DOG1 were positive in 381 (94 %) and 392 (96 %) cases, respectively, showing nearly identical overall sensitivity of ETV1, KIT, and DOG1 for GISTs. In addition, ETV1 expression was positively correlated with that of KIT. Notably, ETV1 was positive in 15 of 26 (58 %) KIT-negative GISTs and even positive in 2 cases of GIST negative for KIT and DOG1, whereas only 6 (5 %) non-GIST mesenchymal GI tumors expressed ETV1. We conclude that ETV1 is specifically expressed in the majority of GISTs, even in some KIT-negative cases, suggesting that ETV1 may be useful as ancillary marker in diagnostically difficult select cases of GIST.

Quercetin targets hnRNPA1 to overcome enzalutamide resistance in prostate cancer cells.

Mol Cancer Ther.

2017 Jul 20

Tummala R, Lou W, Gao AC, Nadiminty N.
PMID: 28729398 | DOI: 10.1158/1535-7163.MCT-17-0030

Prostate cancer remains dependent on androgen receptor signaling even after castration. Aberrant androgen receptor signaling in castration resistant prostate cancer is mediated by mechanisms such as alterations in the androgen receptor and activation of interacting signaling pathways. Clinical evidence confirms that resistance to the next generation anti-androgen, enzalutamide, may be mediated to a large extent by alternative splicing of the androgen receptor to generate constitutively active splice variants such as AR-V7. The splice variants AR-V7 and Arv567es have been implicated in the resistance to not only enzalutamide, but also to abiraterone and other conventional therapeutics such as taxanes. Numerous studies including ours suggest that splicing factors such as hnRNPA1 promote the generation of AR-V7, thus contributing to enzalutamide resistance in prostate cancer cells. In the present study, we discovered that quercetin, a naturally occurring polyphenolic compound, reduces the expression of hnRNPA1, and consequently, that of AR-V7. The suppression of AR-V7 by quercetin resensitizes enzalutamide-resistant prostate cancer cells to treatment with enzalutamide. Our results indicate that quercetin downregulates hnRNPA1 expression, downregulates the expression of AR-V7, antagonizes androgen receptor signaling, and resensitizes enzalutamide-resistant prostate cancer cells to enzalutamide treatment in vivo in mouse xenografts. These findings demonstrate that suppressing the alternative splicing of the androgen receptor may have important implications in overcoming the resistance to next-generation anti-androgen therapy.

Expression pattern of androgen receptor and AR-V7 in androgen deprivation therapy naïve salivary duct carcinomas

Hum Pathol.

2018 Sep 26

Yang RK, Zhao P, Lu C, Luo J, Hu R.
PMID: 30267779 | DOI: 10.1016/j.humpath.2018.09.009

Androgen deprivation therapy (ADT) has been used to treat salivary duct carcinoma (SDC). The androgen receptor splice variant-7 (AR-V7) has been detected in castration-resistant prostate cancer (CRPC) and implicated in resistance to androgen receptor (AR)-targeted therapies. Given the potential role of AR/AR-V7 in SDC treatment, this study focuses on AR/AR-V7 expression in SDC specimens collected prior to ADT. RNA in situ hybridization (ISH) and immunohistochemistry (IHC) to detect total AR and AR-V7 were performed on formalin-fixed, paraffin-embedded SDC specimens from 23 patients. Full length AR (AR-FL) and AR-V7 transcripts were quantified in a subset of tumors by reverse transcription polymerase chain reaction (RT-PCR). Twenty SDCs were positive for total AR by ISH and IHC. Among AR positive SDCs, 70% (14/20) were positive for AR-V7 mRNA by ISH, while 15% (3/20) were positive for AR-V7 protein by IHC. The three SDCs which expressed the highest levels of AR-V7 were all from female patients; one of them expressed significant amount of AR-V7 and barely detectable AR-FL transcripts by RT-PCR. Immunohistochemistry expression of Forkhead box protein A1, prostate-specific antigen, prostatic acid phosphatase, NKX3.1 was observed in some SDCs regardless of patient gender. Five SDCs demonstrated strong human epidermal growth factor receptor 2 (HER2) expression. We conclude that treatment-naïve SDCs may express AR-V7 at levels comparable to or even exceeding the levels detected in CRPC. Our data support the feasibility to incorporate AR-V7 assessment via ISH and/or IHC in the ongoing clinical trials evaluating the therapeutic benefit of AR targeted therapies in SDC patients.

Snail promotes resistance to enzalutamide through regulation of androgen receptor activity in prostate cancer.

Oncotarget.

2016 Jul 07

Ware KE, Somarelli JA, Schaeffer D, Li J, Zhang T, Park S, Patierno SR, Freedman J, Garcia-Blanco MA, Armstrong AJ.
PMID: 27409172 | DOI: 10.18632/oncotarget.10476

Treatment with androgen-targeted therapies can induce upregulation of epithelial plasticity pathways. Epithelial plasticity is known to be important for metastatic dissemination and therapeutic resistance. The goal of this study is to elucidate the functional consequence of induced epithelial plasticity on AR regulation during disease progression to identify factors important for treatment-resistant and metastatic prostate cancer. We pinpoint the epithelial plasticity transcription factor, Snail, at the nexus of enzalutamide resistance and prostate cancer metastasis both in preclinical models of prostate cancer and in patients. In patients, Snail expression is associated with Gleason 9-10 high-risk disease and is strongly overexpressed in metastases as compared to localized prostate cancer. Snail expression is also elevated in enzalutamide-resistant prostate cancer cells compared to enzalutamide-sensitive cells, and downregulation of Snail re-sensitizes enzalutamide-resistant cells to enzalutamide. While activation of Snail increases migration and invasion, it is also capable of promoting enzalutamide resistance in enzalutamide-sensitive cells. This Snail-mediated enzalutamide resistance is a consequence of increased full-length AR and AR-V7 expression and nuclear localization. Downregulation of either full-length AR or AR-V7 re-sensitizes cells to enzalutamide in the presence of Snail, thus connecting Snail-induced enzalutamide resistance directly to AR biology. Finally, we demonstrate that Snail is capable of mediating-resistance through AR even in the absence of AR-V7. These findings imply that increased Snail expressionduring progression to metastatic disease may prime cells for resistance to AR-targeted therapies by promoting AR activity in prostate cancer.

The Utility of ETV1, ETV4, and ETV5 RNA In Situ Hybridization in the Diagnosis of CIC-DUX4 Sarcomas

Histopathology.

2016 Oct 27

Smith SC, Palanisamy N, Martin E, Almenara J, McHugh JB, Choi EK, Lucas DR, Betz BL, Thomas D, Patel RM.
PMID: 27790742 | DOI: 10.1111/his.13112

Abstract

AIMS:

A recently characterized group of undifferentiated small round cell sarcomas harbours fusions of the genes CIC and DUX4. Studies report a distinctive gene expression profile for these sarcomas, including expression of E26 transformation specific (ETS)-family protooncogenic transcription factors ETV1, ETV4, and ETV5. To test the utility of an ancillary diagnostic technique for these tumors, we evaluated chromogenic RNA in situ hybridization assays for ETV1, ETV4, and ETV5, as diagnostic adjuncts for this emerging group of highly malignant sarcomas.

METHODS AND RESULTS:

We tested 6 confirmed CIC-DUX4 sarcomas and 105 lesions in the differential, including 48 Ewing sarcomas for expression of ETV1, ETV4, and ETV5, scoring expression utilizing a previously validated scale. ETV1 and ETV4 were positive in 5/6 cases, while ETV5 was positive in 6/6. No Ewing sarcoma or other sarcoma tested, showed co-expression of these transcripts, while one ETV1, ETV4, ETV5 positive previously unclassified round cell sarcoma, was identified as harboring a CIC rearrangement by break-apart FISH.

CONCLUSION:

We identified overexpression of ETV1, ETV4, and ETV5 transcripts in situ in CIC-DUX4 sarcomas using a robust assay in routine archival sections. One previously unclassified round cell sarcoma showed ETV1/4/5 positivity, and was proven to harbor a CIC rearrangement by break-apart FISH. The sensitivity and specificity observed with our in situ hybridization assay implies potential utility as an ancillary diagnostic technique, particularly when faced with limited biopsy samples.

Novel Junction-specific and Quantifiable In Situ Detection of AR-V7 and its Clinical Correlates in Metastatic Castration-resistant Prostate Cancer.

Eur Urol.

2017 Aug 30

Zhu Y, Sharp A, Anderson CM, Silberstein JL, Taylor M, Lu C, Zhao P, De Marzo AM, Antonarakis ES, Wang M, Wu X, Luo Y, Su N, Nava Rodrigues D, Figueiredo I, Welti J, Park E, Ma XJ, Coleman I, Morrissey C, Plymate SR, Nelson PS, de Bono JS, Luo J
PMID: 28866255 | DOI: 10.1016/j.eururo.2017.08.009

Abstract

BACKGROUND:

Androgen receptor splice variant 7 (AR-V7) has been implicated in resistance to abiraterone and enzalutamide treatment in men with metastatic castration-resistant prostate cancer (mCRPC). Tissue- or cell-based in situ detection of AR-V7, however, has been limited by lack of specificity.

OBJECTIVE:

To address current limitations in precision measurement of AR-V7 by developing a novel junction-specific AR-V7 RNA in situ hybridization (RISH) assay compatible with automated quantification.

DESIGN, SETTING, AND PARTICIPANTS:

We designed a RISH method to visualize single splice junctions in cells and tissue. Using the validated assay for junction-specific detection of the full-length AR (AR-FL) and AR-V7, we generated quantitative data, blinded to clinical data, for 63 prostate tumor biopsies.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:

We evaluated clinical correlates of AR-FL/AR-V7 measurements, including association with prostate-specific antigen progression-free survival (PSA-PFS) and clinical and radiographic progression-free survival (PFS), in a subset of patients starting treatment with abiraterone or enzalutamide following biopsy.

RESULTS AND LIMITATIONS:

Quantitative AR-FL/AR-V7 data were generated from 56 of the 63 (88.9%) biopsy specimens examined, of which 44 were mCRPC biopsies. Positive AR-V7 signals were detected in 34.1% (15/44) mCRPC specimens, all of which also co-expressed AR-FL. The median AR-V7/AR-FL ratio was 11.9% (range 2.7-30.3%). Positive detection of AR-V7 was correlated with indicators of high disease burden at baseline. Among the 25 CRPC biopsies collected before treatment with abiraterone or enzalutamide, positive AR-V7 detection, but not higher AR-FL, was significantly associated with shorter PSA-PFS (hazard ratio 2.789, 95% confidence interval 1.12-6.95; p=0.0081).

CONCLUSIONS:

We report for the first time a RISH method for highly specific and quantifiable detection of splice junctions, allowing further characterization of AR-V7 and its clinical significance.

PATIENT SUMMARY:

Higher AR-V7 levels detected and quantified using a novel method were associated with poorer response to abiraterone or enzalutamide in prostate cancer.

Analytical Validation and Clinical Qualification of a New Immunohistochemical Assay for Androgen Receptor Splice Variant-7 Protein Expression in Metastatic Castration-resistant Prostate Cancer

European Urology

2016 Apr 23

Jonathan Welti J, Rodrigues DN, Sharp A, Sun S, Lorentea D, Riisnaes R, Figueiredo I, Zafeiriou Z, Rescigno P, de Bono JS, Plymate SR.
PMID: - | DOI: 10.1016/j.eururo.2016.03.049

Abstract

Background
The androgen receptor splice variant-7 (AR-V7) has been implicated in the development of castration-resistant prostate cancer (CRPC) and resistance to abiraterone and enzalutamide.

Objective
To develop a validated assay for detection of AR-V7 protein in tumour tissue and determine its expression and clinical significance as patients progress from hormone-sensitive prostate cancer (HSPC) to CRPC.

Design, setting, and participants
Following monoclonal antibody generation and validation, we retrospectively identified patients who had HSPC and CRPC tissue available for AR-V7 immunohistochemical (IHC) analysis.

Outcome measurements and statistical analysis
Nuclear AR-V7 expression was determined using IHC H score (HS) data. The change in nuclear AR-V7 expression from HSPC to CRPC and the association between nuclear AR-V7 expression and overall survival (OS) was determined.

Results and limitations
Nuclear AR-V7 expression was significantly lower in HSPC (median HS 50, interquartile range [IQR] 17.5–90) compared to CRPC (HS 135, IQR 80–157.5; p < 0.0001), and in biopsy tissue taken before (HS 80, IQR 30–136.3) compared to after (HS 140, IQR 105–167.5; p = 0.007) abiraterone or enzalutamide treatment. Lower nuclear AR-V7 expression at CRPC biopsy was associated with longer OS (hazard ratio 1.012, 95% confidence interval 1.004–1.020; p = 0.003). While this monoclonal antibody primarily binds to AR-V7 in PC biopsy tissue, it may also bind to other proteins.

Conclusions
We provide the first evidence that nuclear AR-V7 expression increases with emerging CRPC and is prognostic for OS, unlike antibody staining for the AR N-terminal domain. These data indicate that AR-V7 is important in CRPC disease biology; agents targeting AR splice variants are needed to test this hypothesis and further improve patient outcome from CRPC.

Patient summary
In this study we found that levels of the protein AR-V7 were higher in patients with advanced prostate cancer. A higher level of AR-V7 identifies a group of patients who respond less well to certain prostate cancer treatments and live for a shorter period of time.

Interaction of the Androgen Receptor, ETV1, and PTEN Pathways in Mouse Prostate Varies with Pathological Stage and Predicts Cancer Progression.

Horm Cancer. 2015 Jan 29.

Higgins J, Brogley M, Palanisamy N, Mehra R, Ittmann MM, Li JZ, Tomlins SA, Robins DM.
PMID: 25631336

To examine the impact of common somatic mutations in prostate cancer (PCa) on androgen receptor (AR) signaling, mouse models were designed to perturb sequentially the AR, ETV1, and PTEN pathways. Mice with "humanized" AR (hAR) alleles that modified AR transcriptional strength by varying polyglutamine tract (Q-tract) length were crossed with mice expressing a prostate-specific, AR-responsive ETV1 transgene (ETV1 Tg ). While hAR allele did not grossly affect ETV1-induced neoplasia, ETV1 strongly antagonized global AR regulation and repressed critical androgen-induced differentiation and tumor suppressor genes, such as Nkx3-1 and Hoxb13. When Pten was varied to determine its impact on disease progression, mice lacking one Pten allele (Pten +/- ) developed more frequent prostatic intraepithelial neoplasia (PIN). Yet, only those with the ETV1 transgene progressed to invasive adenocarcinoma. Furthermore, progression was more frequent with the short Q-tract (stronger) AR, suggesting that the AR, ETV1, and PTEN pathways cooperate in aggressive disease. On the Pten +/- background, ETV1 had markedly less effect on AR target genes. However, a strong inflammatory gene expression signature, notably upregulation of Cxcl16, was induced by ETV1. Comparison of mouse and human patient data stratified by the presence of E26 transformation-specific ETS fusion genes highlighted additional factors, some not previously associated with prostate cancer but for which targeted therapies are in development for other diseases. In sum, concerted use of these mouse models illuminates the complex interplay of AR, ETV1, and PTEN pathways in pre-cancerous neoplasia and early tumorigenesis, disease stages difficult to analyze in man.

Detection of AR-V7 transcript with RNA in situ hybridization in human salivary duct cancer

Oral Oncology

2018 Jun 28

Kang H, Antonarakis ES, Luo J, Zheng Q, Rooper L, De Marzo AM, Westra WH, Lotan TL.
PMID: - | DOI: 10.1016/j.oraloncology.2018.06.026

The androgen receptor (AR) is a nuclear steroid receptor that binds to testosterone and dihydrotestosterone and regulates the transcription of genes leading to cell growth, differentiation and survival. AR serves as an important oncogenic signal in prostate cancers and apocrine breast cancers. Salivary duct carcinoma (SDC) is a rare subtype of head and neck cancer that is defined by an apocrine phenotype, with AR positivity by immunohistochemistry (IHC) in up to 98% of cases [1]. A recent clinical trial with leuprorelin acetate and bicalutamide has shown promising activity with an overall response rate of 42% in AR-positive salivary gland cancers, but further analyses of clinicopathological factors or biomarkers including AR expression intensity, HER2 expression, EGFR expression and HRAS mutation did not show any significant association with outcomes [2].

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	Description
sense Example: Hs-LAG3-sense	Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe.
Intron# Example: Mm-Htt-intron2	Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection
Pool/Pan Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G)	A mixture of multiple probe sets targeting multiple genes or transcripts
No-XSp Example: Hs-PDGFB-No-XMm	Does not cross detect with the species (Sp)
XSp Example: Rn-Pde9a-XMm	designed to cross detect with the species (Sp)
O# Example: Mm-Islr-O1	Alternative design targeting different regions of the same transcript or isoforms
CDS Example: Hs-SLC31A-CDS	Probe targets the protein-coding sequence only
EnEm	Probe targets exons n and m
En-Em	Probe targets region from exon n to exon m
Retired Nomenclature
tvn Example: Hs-LEPR-tv1	Designed to target transcript variant n
ORF Example: Hs-ACVRL1-ORF	Probe targets open reading frame
UTR Example: Hs-HTT-UTR-C3	Probe targets the untranslated region (non-protein-coding region) only
5UTR Example: Hs-GNRHR-5UTR	Probe targets the 5' untranslated region only
3UTR Example: Rn-Npy1r-3UTR	Probe targets the 3' untranslated region only
Pan Example: Pool	A mixture of multiple probe sets targeting multiple genes or transcripts

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Probes for INS

Content for comparison

Gene

Product

Research area

Category

Abstract

PURPOSE:

EXPERIMENTAL DESIGN:

RESULTS:

CONCLUSIONS:

Abstract

AIMS:

METHODS AND RESULTS:

CONCLUSION:

Abstract

Background
The androgen receptor splice variant-7 (AR-V7) has been implicated in the development of castration-resistant prostate cancer (CRPC) and resistance to abiraterone and enzalutamide.

Objective
To develop a validated assay for detection of AR-V7 protein in tumour tissue and determine its expression and clinical significance as patients progress from hormone-sensitive prostate cancer (HSPC) to CRPC.

Design, setting, and participants
Following monoclonal antibody generation and validation, we retrospectively identified patients who had HSPC and CRPC tissue available for AR-V7 immunohistochemical (IHC) analysis.

Outcome measurements and statistical analysis
Nuclear AR-V7 expression was determined using IHC H score (HS) data. The change in nuclear AR-V7 expression from HSPC to CRPC and the association between nuclear AR-V7 expression and overall survival (OS) was determined.

Patient summary
In this study we found that levels of the protein AR-V7 were higher in patients with advanced prostate cancer. A higher level of AR-V7 identifies a group of patients who respond less well to certain prostate cancer treatments and live for a shorter period of time.

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Advanced Cell Diagnostics

Bio-Techne

Advanced Cell Diagnostics China

Probes for INS

Content for comparison

Gene

Product

Research area

Category

Abstract

PURPOSE:

EXPERIMENTAL DESIGN:

RESULTS:

CONCLUSIONS:

Abstract

AIMS:

METHODS AND RESULTS:

CONCLUSION:

Abstract

BackgroundThe androgen receptor splice variant-7 (AR-V7) has been implicated in the development of castration-resistant prostate cancer (CRPC) and resistance to abiraterone and enzalutamide.

ObjectiveTo develop a validated assay for detection of AR-V7 protein in tumour tissue and determine its expression and clinical significance as patients progress from hormone-sensitive prostate cancer (HSPC) to CRPC.

Design, setting, and participantsFollowing monoclonal antibody generation and validation, we retrospectively identified patients who had HSPC and CRPC tissue available for AR-V7 immunohistochemical (IHC) analysis.

Outcome measurements and statistical analysisNuclear AR-V7 expression was determined using IHC H score (HS) data. The change in nuclear AR-V7 expression from HSPC to CRPC and the association between nuclear AR-V7 expression and overall survival (OS) was determined.

Patient summaryIn this study we found that levels of the protein AR-V7 were higher in patients with advanced prostate cancer. A higher level of AR-V7 identifies a group of patients who respond less well to certain prostate cancer treatments and live for a shorter period of time.

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Advanced Cell Diagnostics

Bio-Techne

Advanced Cell Diagnostics China

Background
The androgen receptor splice variant-7 (AR-V7) has been implicated in the development of castration-resistant prostate cancer (CRPC) and resistance to abiraterone and enzalutamide.

Objective
To develop a validated assay for detection of AR-V7 protein in tumour tissue and determine its expression and clinical significance as patients progress from hormone-sensitive prostate cancer (HSPC) to CRPC.

Design, setting, and participants
Following monoclonal antibody generation and validation, we retrospectively identified patients who had HSPC and CRPC tissue available for AR-V7 immunohistochemical (IHC) analysis.

Outcome measurements and statistical analysis
Nuclear AR-V7 expression was determined using IHC H score (HS) data. The change in nuclear AR-V7 expression from HSPC to CRPC and the association between nuclear AR-V7 expression and overall survival (OS) was determined.

Patient summary
In this study we found that levels of the protein AR-V7 were higher in patients with advanced prostate cancer. A higher level of AR-V7 identifies a group of patients who respond less well to certain prostate cancer treatments and live for a shorter period of time.