A 12-Gene Expression Signature Is Associated with Aggressive Histological in Prostate Cancer

Agell, Laia; Hernández, Sílvia; Nonell, Lara; Lorenzo, Marta; Puigdecanet, Eulàlia; Muga, Silvia de; Juanpere, Núria; Bermudo, Raquel; Fernández, Pedro; Lorente, José A.; Serrano, Sergio; Lloreta, Josep

doi:10.1016/j.ajpath.2012.08.005

Cited by 43 publications

(37 citation statements)

References 38 publications

(49 reference statements)

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“…To evaluate the clinical relevance of HNRNPL and its RNA targets, we analyzed the mRNA expression of HNRNPL in several independent prostate cancer cohorts (38)(39)(40)(41). HNRNPL expression is consistently higher in prostate tumors versus normal prostate (Fig.…”

Section: Hnrnpl and Its Rna Targets Are Clinically Relevant In Humanmentioning

confidence: 99%

Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing

Teng

Chen

Xiao

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

260

221

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Alternative RNA splicing plays an important role in cancer. To determine which factors involved in RNA processing are essential in prostate cancer, we performed a genome-wide CRISPR/Cas9 knockout screen to identify the genes that are required for prostate cancer growth. Functional annotation defined a set of essential spliceosome and RNA binding protein (RBP) genes, including most notably heterogeneous nuclear ribonucleoprotein L (HNRNPL). We defined the HNRNPL-bound RNA landscape by RNA immunoprecipitation coupled with next-generation sequencing and linked these RBP-RNA interactions to changes in RNA processing. HNRNPL directly regulates the alternative splicing of a set of RNAs, including those encoding the androgen receptor, the key lineage-specific prostate cancer oncogene. HNRNPL also regulates circular RNA formation via back splicing. Importantly, both HNRNPL and its RNA targets are aberrantly expressed in human prostate tumors, supporting their clinical relevance. Collectively, our data reveal HNRNPL and its RNA clients as players in prostate cancer growth and potential therapeutic targets.CRISPR screen | HNRNPL | prostate cancer | RNA binding protein | alternative splicing P rostate cancer is among the most prevalent adult malignancies in developed countries. The principal treatment for prostate cancer once it is no longer amenable to surgery or radiation treatment is androgen deprivation therapy, which targets androgen or androgen receptor (AR) signaling. However, resistance to androgen deprivation therapy often develops and leads to a state termed "castration-resistant prostate cancer," which still lacks an effective cure (1-3). Therefore, significant efforts have been devoted to better understand the mechanism of oncogenesis and to develop additional effective therapeutics targeting pivotal oncogenes, cancer-related signal transduction pathways, and epigenetic regulators (4, 5).Alternative RNA splicing is a fundamental cellular process by which a single gene can give rise to multiple different transcripts and proteins. This process is tightly regulated by core spliceosomes and other splicing factors, such as the serine/ arginine-rich family of proteins and heterogeneous nuclear ribonucleoproteins (hnRNPs) (6, 7). Multiple studies indicate that deregulation of alternative splicing is implicated in cancer progression and that the splicing machinery may be targeted therapeutically (8-10). In addition to RNA splicing, the physical interactions between RNAs and RNA binding proteins (RBPs) underlie multiple RNA processing steps, such as capping, polyadenylation, transport, localization, modification, and translation, thereby regulating many aspects of RNA fate (11).Which RBPs and their related RNA processing steps are functionally important, especially in prostate cancer, remains elusive.The recent implementation of the clustered regularly interspaced short palindromic repeats (CRISPR)-associated nuclease Cas9 genome editing system has proved effective in high-throughput lossof-function screens (12)(13)(14)...

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Section: Hnrnpl and Its Rna Targets Are Clinically Relevant In Humanmentioning

confidence: 99%

Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing

Teng

Chen

Xiao

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

260

221

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“…The ability to use miRNA and mRNA targets to distinguish indolent vs. aggressive disease has also received attention (Pickl et al ., 2014). A 12‐gene tissue expression signature has previously been described in association with aggressive histology in PCa distinguishing low‐grade from high‐grade tumours (Agell et al ., 2012). For the transcriptomic analysis of the current study, we identified a 33‐gene panel compiled by a comprehensive meta‐analysis of the literature.…”

Section: Discussionmentioning

confidence: 99%

Integrating biomarkers across omic platforms: an approach to improve stratification of patients with indolent and aggressive prostate cancer

Murphy

Boyce

et al. 2018

Molecular Oncology

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Classifying indolent prostate cancer represents a significant clinical challenge. We investigated whether integrating data from different omic platforms could identify a biomarker panel with improved performance compared to individual platforms alone. DNA methylation, transcripts, protein and glycosylation biomarkers were assessed in a single cohort of patients treated by radical prostatectomy. Novel multiblock statistical data integration approaches were used to deal with missing data and modelled via stepwise multinomial logistic regression, or LASSO. After applying leave‐one‐out cross‐validation to each model, the probabilistic predictions of disease type for each individual panel were aggregated to improve prediction accuracy using all available information for a given patient. Through assessment of three performance parameters of area under the curve (AUC) values, calibration and decision curve analysis, the study identified an integrated biomarker panel which predicts disease type with a high level of accuracy, with Multi AUC value of 0.91 (0.89, 0.94) and Ordinal C‐Index (ORC) value of 0.94 (0.91, 0.96), which was significantly improved compared to the values for the clinical panel alone of 0.67 (0.62, 0.72) Multi AUC and 0.72 (0.67, 0.78) ORC. Biomarker integration across different omic platforms significantly improves prediction accuracy. We provide a novel multiplatform approach for the analysis, determination and performance assessment of novel panels which can be applied to other diseases. With further refinement and validation, this panel could form a tool to help inform appropriate treatment strategies impacting on patient outcome in early stage prostate cancer.

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“…The ERG gene, as a highly prevalent fusion partner in PCa, also showed a positive association with both a high Gleason score and short survival in several different study settings [84,85,106]. Multiple studies have demonstrated that AMACR, a gene that encodes an enzyme that functions in breaking down fatty acids and certain toxic compounds, is overexpressed in groups with adverse outcomes [31,47,61,111].…”

Section: Resultsmentioning

confidence: 99%

“…After literature screening, 12 reviews [7,8,9,10,11,12,13,14,15,16,17,18] and 137 research papers [19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102...…”

Section: Resultsmentioning

confidence: 99%

Trends in Gene Expression Profiling for Prostate Cancer Risk Assessment: A Systematic Review

et al. 2017

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Objectives: The aim of the study is to review biotechnology advances in gene expression profiling on prostate cancer (PCa), focusing on experimental platform development and gene discovery, in relation to different study designs and outcomes in order to understand how they can be exploited to improve PCa diagnosis and clinical management. Methods: We conducted a systematic literature review on gene expression profiling studies through PubMed/MEDLINE and Web of Science between 2000 and 2016. Tissue biopsy and clinical gene profiling studies with different outcomes (e.g., recurrence, survival) were included. Results: Over 3,000 papers were screened and 137 full-text articles were selected. In terms of technology used, microarray is still the most popular technique, increasing from 50 to 70% between 2010 and 2015, but there has been a rise in the number of studies using RNA sequencing (13% in 2015). Sample sizes have increased, as well as the number of genes that can be screened all at once, but we have also observed more focused targeting in more recent studies. Qualitative analysis on the specific genes found associated with PCa risk or clinical outcomes revealed a large variety of gene candidates, with a few consistent cross-studies. Conclusions: The last 15 years of research in gene expression in PCa have brought a large volume of data and information that has been decoded only in part, but advancements in high-throughput sequencing technology are increasing the amount of data that can be generated. The variety of findings warrants the execution of both validation studies and meta-analyses. Genetic biomarkers have tremendous potential for early diagnosis of PCa and, if coupled with other diagnostics (e.g., imaging), can effectively be used to concretize less-invasive, personalized prediction of PCa risk and progression.

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A 12-Gene Expression Signature Is Associated with Aggressive Histological in Prostate Cancer

Cited by 43 publications

References 38 publications

Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing

Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing

Integrating biomarkers across omic platforms: an approach to improve stratification of patients with indolent and aggressive prostate cancer

Trends in Gene Expression Profiling for Prostate Cancer Risk Assessment: A Systematic Review

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