Dataset Information

UroMark-a urinary biomarker assay for the detection of bladder cancer.

ABSTRACT: Bladder cancer (BC) is one of the most common cancers in the western world and ranks as the most expensive to manage, due to the need for cystoscopic examination. BC shows frequent changes in DNA methylation, and several studies have shown the potential utility of urinary biomarkers by detecting epigenetic alterations in voided urine. The aim of this study is to develop a targeted bisulfite next-generation sequencing assay to diagnose BC from urine with high sensitivity and specificity.We defined a 150 CpG loci biomarker panel from a cohort of 86 muscle-invasive bladder cancers and 30 normal urothelium. Based on this panel, we developed the UroMark assay, a next-generation bisulphite sequencing assay and analysis pipeline for the detection of bladder cancer from urinary sediment DNA. The 150 loci UroMark assay was validated in an independent cohort (n?=?274, non-cancer (n?=?167) and bladder cancer (n?=?107)) voided urine samples with an AUC of 97%. The UroMark classifier sensitivity of 98%, specificity of 97% and NPV of 97% for the detection of primary BC was compared to non-BC urine.Epigenetic urinary biomarkers for detection of BC have the potential to revolutionise the management of this disease. In this proof of concept study, we show the development and utility of a novel high-throughput, next-generation sequencing-based biomarker for the detection of BC-specific epigenetic alterations in urine.

SUBMITTER: Feber A

PROVIDER: S-EPMC5282868 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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UroMark-a urinary biomarker assay for the detection of bladder cancer.

Feber Andrew A Dhami Pawan P Dong Liqin L de Winter Patricia P Tan Wei Shen WS Martínez-Fernández Mónica M Paul Dirk S DS Hynes-Allen Antony A Rezaee Sheida S Gurung Pratik P Rodney Simon S Mehmood Ahmed A Villacampa Felipe F de la Rosa Federico F Jameson Charles C Cheng Kar Keung KK Zeegers Maurice P MP Bryan Richard T RT James Nicholas D ND Paramio Jesus M JM Freeman Alex A Beck Stephan S Kelly John D JD

Clinical epigenetics 20170131

<h4>Background</h4>Bladder cancer (BC) is one of the most common cancers in the western world and ranks as the most expensive to manage, due to the need for cystoscopic examination. BC shows frequent changes in DNA methylation, and several studies have shown the potential utility of urinary biomarkers by detecting epigenetic alterations in voided urine. The aim of this study is to develop a targeted bisulfite next-generation sequencing assay to diagnose BC from urine with high sensitivity and sp ...[more]

PMID: 28163793

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Project description:BackgroundThe objective of this study was to evaluate Octamer-binding transcription factor 4 (Oct-4), neutrophil to lymphocyte ratio (NLR) and body mass index (BMI) as independent prognostic biomarkers for prediction of urinary bladder cancer (UBC) outcomes. With the advancement in prognostic biomarker discovery, tumor recurrence is difficult to accurately predict in UBC. UBC is costly to treat due to the requirement of frequent invasive follow-up sessions. Therefore, it is of utmost importance to evaluate good prognostic biomarkers for UBC surveillance.MethodsWe studied 39 UBC tissue samples. Oct-4 protein expression was evaluated semiquantitatively by immunohistochemistry (IHC). Complete blood count data and body weight as well as the height of the patients were retrieved and recorded before the date of the first transurethral resection of bladder tumor (TURBT). The follow-up period was 48 months for recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS).ResultsOct-4 expression profile was found to be significantly associated with gender (p = 0.028), tumor grade (p = 0.038), tumor stage (p = 0.003), lymph node status (p = 0.029), recurrence (p = 0.004), progression (p = 0.011), and treatment modality (p = 0.016). Tumor grade and progression were found significant with NLR values (tumor grade, p = 0.006; progression, p = 0.038) and BMI (tumor grade, p = 0.036; progression, p = 0.014). Moreover, BMI was also significantly associated with UBC recurrence (p = 0.014). Kaplan-Meier survival analysis showed poor prognosis with both high Oct-4 expression (RFS, p = 0.001; PFS, p = 0.004; OS, p = 0.014) and high NLR values (RFS, p = 0.049; PFS, p = 0.004; OS, p = 0.005). Patients with high BMI too had poor RFS (p = 0.025) and poor PFS (p = 0.032). Furthermore, multivariate Cox regression analysis, indicated Oct-4 as an independent prognostic biomarker for RFS (HR = 0.240, 95% CI, 0.072-0.804, p = 0.021).ConclusionsWe conclude that the expression profile of Oct-4 will be beneficial in prediction of UBC recurrence, and could have profound implications on the development of new therapeutic targets for UBC treatment.

Project description:BACKGROUND:The present study sought to identify a panel of DNA markers for noninvasive diagnosis using cell-free DNA (cfDNA) from urine supernatant or cellular DNA from urine sediments of hematuria patients. A panel of 48 bladder cancer-specific genes was selected. A next-generation sequencing-based assay with a cfDNA barcode-enabled single-molecule test was employed. Mutation profiles of blood, urine, and tumor sample from 16 bladder cancer patients were compared. Next, urinary cellular DNA and cfDNA were prospectively collected from 125 patients (92 bladder cancer cases and 33 controls) and analyzed using the 48-gene panel. The individual gene markers and combinations of markers were validated according to the pathology results. The mean areas under the receiver operating characteristic (ROC) curves (AUCs) obtained with the various modeling approaches were calculated and compared. RESULTS:This pilot study of 16 bladder cancer patients demonstrated that gene mutations in urine supernatant and sediments had better concordance with cancer tissue as compared with plasma. Logistic analyses suggested two powerful combinations of genes for genetic diagnostic modeling: five genes for urine supernatant (TERT, FGFR3, TP53, PIK3CA, and KRAS) and seven genes for urine sediments (TERT, FGFR3, TP53, HRAS, PIK3CA, KRAS, and ERBB2). The accuracy of the five-gene panel and the seven-gene panel in the validation cohort yielded AUCs of 0.94 [95% confidence interval (CI) 0.91-0.97] and 0.91 (95% CI 0.86-0.96), respectively. With the addition of age and gender, the diagnostic power of the urine supernatant five-gene model and the urine sediment seven-gene model improved as the revised AUCs were 0.9656 (95% CI 0.9368-0.9944) and 0.9587 (95% CI 0.9291-0.9883). CONCLUSIONS:cfDNA from urine bears great diagnostic potential. A five-gene panel for urine supernatant and a seven-gene panel for urine sediments are promising options for identifying bladder cancer in hematuria patients.

Dataset Information

UroMark-a urinary biomarker assay for the detection of bladder cancer.

Publications

UroMark-a urinary biomarker assay for the detection of bladder cancer.

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