The molecular underpinnings of prostate cancer: impacts on management and pathology practice

Rodrigues, Daniel Nava; Boysen, Gunther; Sumanasuriya, Semini; Seed, George; Marzo, Angelo M. De; Bono, Johann S. de

doi:10.1002/path.4826

Cited by 41 publications

(30 citation statements)

References 105 publications

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“…Ihre Anwendung wird in ersten, experimentellen Studien beim mCRPC überprüft. Auch der Status von PTEN als prädiktiver Biomarker beim mCRPC ist derzeit Gegenstand einer Phase-II-Studie [21].…”

Section: Aberrationen In Signalkaskadenunclassified

Resistenzentwicklung und prädiktive Marker beim metastasierten Prostatakarzinom

Bernemann¹,

Bögemann²,

Steinestel³

et al. 2017

Oncol Res Treat

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Anders als bei vielen anderen Krebserkrankungen gab es beim Prostatakarzinom lange Zeit keinen Ansatz für eine individualisierte Therapie. Seit der Zulassung von mehreren modernen Wirkstoffen für die Therapie des fortgeschrittenen Stadiums ändert sich dies allmählich. Zunächst galt die Androgenrezeptor-Splice-Variante AR-V7 als vielversprechender Biomarker für die Therapiesteuerung, woran sich zunehmend Zweifel mehren. Inzwischen gibt es jedoch eine Reihe von weiteren neuen, noch nicht zugelassenen und nicht (nur) auf den Androgenrezeptor fokussierenden Therapieansätzen, die auch beim fortgeschrittenen Prostatakarzinom eine personalisierte Medizin wahrscheinlicher machen.

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Section: Aberrationen In Signalkaskadenunclassified

Resistenzentwicklung und prädiktive Marker beim metastasierten Prostatakarzinom

Bernemann¹,

Bögemann²,

Steinestel³

et al. 2017

Oncol Res Treat

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“…Advances in second-generation sequencing technologies ushered in the modern era of personalized medicine [ 1 ]. In cancer, mutations revealed by clinical sequencing have been shown to be vitally useful in achieving better subtype classification, charting appropriate treatment regimens, and identifying novel drug targets [ 2 – 4 ]. One of the well-studied examples is acute myeloid leukemia (AML), for which prognosis and treatment strategies depend on the detection of a wide spectrum of mutations: FLT3 internal tandem application (ITD), MLL partial tandem duplication (PTD), NPM1 insertion, CEBPA insertion/deletions (indels), and gene fusions PML-RARA , RUNX1-RUNX1T and CBFB-MYH11 , among others [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

TAP: a targeted clinical genomics pipeline for detecting transcript variants using RNA-seq data

et al. 2018

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BackgroundRNA-seq is a powerful and cost-effective technology for molecular diagnostics of cancer and other diseases, and it can reach its full potential when coupled with validated clinical-grade informatics tools. Despite recent advances in long-read sequencing, transcriptome assembly of short reads remains a useful and cost-effective methodology for unveiling transcript-level rearrangements and novel isoforms. One of the major concerns for adopting the proven de novo assembly approach for RNA-seq data in clinical settings has been the analysis turnaround time. To address this concern, we have developed a targeted approach to expedite assembly and analysis of RNA-seq data.ResultsHere we present our Targeted Assembly Pipeline (TAP), which consists of four stages: 1) alignment-free gene-level classification of RNA-seq reads using BioBloomTools, 2) de novo assembly of individual targets using Trans-ABySS, 3) alignment of assembled contigs to the reference genome and transcriptome with GMAP and BWA and 4) structural and splicing variant detection using PAVFinder. We show that PAVFinder is a robust gene fusion detection tool when compared to established methods such as Tophat-Fusion and deFuse on simulated data of 448 events. Using the Leucegene acute myeloid leukemia (AML) RNA-seq data and a set of 580 COSMIC target genes, TAP identified a wide range of hallmark molecular anomalies including gene fusions, tandem duplications, insertions and deletions in agreement with published literature results. Moreover, also in this dataset, TAP captured AML-specific splicing variants such as skipped exons and novel splice sites reported in studies elsewhere. Running time of TAP on 100–150 million read pairs and a 580-gene set is one to 2 hours on a 48-core machine.ConclusionsWe demonstrated that TAP is a fast and robust RNA-seq variant detection pipeline that is potentially amenable to clinical applications. TAP is available at http://www.bcgsc.ca/platform/bioinfo/software/pavfinderElectronic supplementary materialThe online version of this article (10.1186/s12920-018-0402-6) contains supplementary material, which is available to authorized users.

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“…6 The AR is bound by testosterone and dihydrotestosterone (DHT), resulting in nuclear localization and activation of target gene transcription. 7 Testosterone suppression as PCa treatment was proposed by Huggins and Hodges in 1941.…”

Section: Introductionmentioning

confidence: 99%

Maximal testosterone suppression in the management of recurrent and metastatic prostate cancer

Klotz

Breau

Collins³

et al. 2017

CUAJ

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Introduction: Testosterone suppression, or androgen-deprivation therapy (ADT), is an established treatment for recurrent and metastatic prostate cancer (PCa). Based on the accuracy and sensitivity of early assays (c. 1960-1970), the castrate testosterone level was set at ≤1.7 nmol/l. Improved sensitivity of testosterone assays shows that both surgical and medical castration can achieve levels <0.7 nmol/l. However, the clinical implications and importance of maximum testosterone suppression remains a subject of controversy. This evidence-based review assesses prospective and retrospective clinical data, linking maximum suppression of testosterone with improved outcomes from ADT. Methods: PubMed and conference proceedings were searched for studies assessing the impact of low testosterone on clinical outcomes from ADT. The key search terms included combinations of prostate cancer and testosterone, predictive/prognostic, and androgen deprivation. Results were limited to studies investigating the relationship between testosterone levels and clinical outcomes. Results: Both prospective and retrospective data support a relationship between testosterone levels below the historical standard of 1.7 nmol/l and improved outcomes. Eight studies showed significant improvements in survival-related outcomes, with the majority of data supporting a testosterone level cutoff of ≤0.7 nmol/l. Conclusions: Tracking both testosterone and prostate-specific antigen (PSA) levels has significant clinical benefits, and the serum testosterone threshold of ≤0.7 nmol/l is a practical goal. The relative levels of testosterone and PSA may indicate continued hormone responsiveness or progression toward castration-resistant prostate cancer (CRPC) and should, therefore, inform treatment strategy. Standardization of assay methods and clinical coordination to facilitate widespread access to state-of the art laboratory equipment is necessary to ensure accurate decision-making.

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The molecular underpinnings of prostate cancer: impacts on management and pathology practice

Cited by 41 publications

References 105 publications

Resistenzentwicklung und prädiktive Marker beim metastasierten Prostatakarzinom

Resistenzentwicklung und prädiktive Marker beim metastasierten Prostatakarzinom

TAP: a targeted clinical genomics pipeline for detecting transcript variants using RNA-seq data

Maximal testosterone suppression in the management of recurrent and metastatic prostate cancer

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