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Urinary expression of genes involved in DNA methylation and histone modification for diagnosis of bladder cancer in patients with asymptomatic microscopic haematuria.

ABSTRACT: The aim of the present study was to identify and test a urine marker panel of genes involved in DNA methylation and histone modification for the detection of urothelial carcinoma of the bladder (UCB). RNA samples obtained from the voided urine of 227 patients with asymptomatic microscopic haematuria (AMH) were analysed. Gene array analysis was performed on 18 randomly selected cDNA samples, which revealed that histone deacetylase 9 (HDAC9), HDAC3, tRNA (cytosine-5-)-methyltransferase1 and DNA methyltransferase 1 were differentially expressed between patients with UCB and control subjects. Subsequently, reverse transcription-quantitative polymerase chain reaction analysis was employed to test the performance of the identified four-gene panel on the remaining 209 cDNA samples. In this targeted discovery cohort, all four genes were significantly associated with UCB on univariable analyses [each odds ratio (OR) >2, P<0.05], but only HDAC3 was significant following multivariable analysis (OR=2.8, P=0.011). The addition of HDAC3 to a base risk factor model improved its accuracy by 1.4%. These data suggest that urinary HDAC3 is associated with the presence of UCB in patients with AMH; however, HDAC3 improved the accuracy of the established risk factors only to a marginal extent.

SUBMITTER: Lucca I

PROVIDER: S-EPMC6540417 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Urinary expression of genes involved in DNA methylation and histone modification for diagnosis of bladder cancer in patients with asymptomatic microscopic haematuria.

Lucca Ilaria I Hofbauer Sebastian L SL Haitel Andrea A Susani Martin M Shariat Shahrokh F SF Klatte Tobias T De Martino Michela M

Oncology letters 20190507 1

The aim of the present study was to identify and test a urine marker panel of genes involved in DNA methylation and histone modification for the detection of urothelial carcinoma of the bladder (UCB). RNA samples obtained from the voided urine of 227 patients with asymptomatic microscopic haematuria (AMH) were analysed. Gene array analysis was performed on 18 randomly selected cDNA samples, which revealed that histone deacetylase 9 (<i>HDAC9</i>)<i>, HDAC3, tRNA (cytosine-5-)-methyltransferase1< ...[more]

PMID: 31289472

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Project description:ObjectivesTo determine the diagnostic accuracy of urinary cytology to diagnose bladder cancer and upper tract urothelial cancer (UTUC) as well as the outcome of patients with a positive urine cytology and normal haematuria investigations in patients in a multicentre prospective observational study of patients investigated for haematuria.Patient and methodsThe DETECT I study (clinicaltrials.gov NCT02676180) recruited patients presenting with haematuria following referral to secondary case at 40 hospitals. All patients had a cystoscopy and upper tract imaging (renal bladder ultrasound [RBUS] and/ or CT urogram [CTU]). Patients, where urine cytology were performed, were sub-analysed. The reference standard for the diagnosis of bladder cancer and UTUC was histological confirmation of cancer. A positive urine cytology was defined as a urine cytology suspicious for neoplastic cells or atypical cells.ResultsOf the 3 556 patients recruited, urine cytology was performed in 567 (15.9%) patients from nine hospitals. Median time between positive urine cytology and endoscopic tumour resection was 27 (IQR: 21.3-33.8) days. Bladder cancer was diagnosed in 39 (6.9%) patients and UTUC in 8 (1.4%) patients. The accuracy of urinary cytology for the diagnosis of bladder cancer and UTUC was: sensitivity 43.5%, specificity 95.7%, positive predictive value (PPV) 47.6% and negative predictive value (NPV) 94.9%. A total of 21 bladder cancers and 5 UTUC were missed. Bladder cancers missed according to grade and stage were as follows: 4 (19%) were ≥ pT2, 2 (9.5%) were G3 pT1, 10 (47.6%) were G3/2 pTa and 5 (23.8%) were G1 pTa. High-risk cancer was confirmed in 8 (38%) patients. There was a marginal improvement in sensitivity (57.7%) for high-risk cancers. When urine cytology was combined with imaging, the diagnostic performance improved with CTU (sensitivity 90.2%, specificity 94.9%) superior to RBUS (sensitivity 66.7%, specificity 96.7%). False positive cytology results were confirmed in 22 patients, of which 12 (54.5%) had further invasive tests and 5 (22.7%) had a repeat cytology. No cancer was identified in these patients during follow-up.ConclusionsUrine cytology will miss a significant number of muscle-invasive bladder cancer and high-risk disease. Our results suggest that urine cytology should not be routinely performed as part of haematuria investigations. The role of urine cytology in select cases should be considered in the context of the impact of a false positive result leading to further potentially invasive tests conducted under general anaesthesia.

Project description:ObjectiveInappropriate diagnosis and treatment of asymptomatic bacteriuria (ASB) and urinary tract infection (UTI) are leading causes of antibiotic overuse but have not been well-studied in patients with risks for complicated UTI such as neurogenic bladder (NB). Our aim was to describe ASB and UTI management in patients with NB and assess factors associated with inappropriate management.DesignRetrospective cohort study.SettingFour Department of Veteran's Affairs (VA) medical centers.ParticipantsAdults with NB due to spinal cord injury/disorder (SCI/D), multiple sclerosis (MS), or Parkinson disease (PD) and encounters with an ASB or UTI diagnosis between 2017 and 2018. Clinical and encounter data were extracted from the VA Corporate Data Warehouse and medical record reviews for a stratified sample of 300 encounters from N=291 patients.InterventionsNone.Main outcome measuresPrevalence of appropriate and inappropriate ASB and UTI diagnosis and treatment was summarized. Multivariable logistic regression models assessed factors associated with inappropriate management.ResultsN=200 UTI and N=100 ASB encounters were included for the 291 unique patients (SCI/D, 39.9%; MS, 36.4%; PD, 23.7%). Most patients were men (83.3%), >65 years (62%), and used indwelling or intermittent catheterization (68.3%). Nearly all ASB encounters had appropriate diagnosis (98%). 70 (35%) UTI encounters had inappropriate diagnosis, including 55 (27.5%) with true ASB, all with inappropriate treatment. Among the remaining 145 UTI encounters, 54 (27%) had inappropriate treatment. Peripheral vascular disease, chronic kidney disease, and cerebrovascular disease were associated with increased odds of inappropriate management; indwelling catheter (aOR 0.35, P=.01) and Physical Medicine & Rehabilitation provider (aOR 0.29, P<.01) were associated with decreased odds.ConclusionUp to half of UTI encounters for patients with NB had inappropriate management, largely due to inappropriate UTI diagnosis in patients with true ASB. Interventions to improve ASB and UTI management in patients with NB should target complex patients with comorbidities being seen by non-rehabilitation providers.

Project description:BackgroundCurrently, the clinical strategy for diagnosis of non-muscle invasive bladder cancer (NMIBC) such as cystoscopy and cytology are invasive and/or with limited accuracy. OncoUrine, a urinary assay for mutation and methylation biomarkers, have showed a high accuracy in the detection of upper tract urinary carcinoma (UTUC) patients with hematuria. The aim of this study is to evaluate the performance of OncoUrine in diagnosis of NMIBC patients.MethodsIn this multicenter prospective study, a total of 203 patients were enrolled, including 60 patients present with hematuria and 143 NMIBC patients under recurrence surveillance. Urine samples were collected before cystoscopy to undergo OncoUrine test. OncoUrine performance was calculated compared to clinical standard methods in hematuria cohort and recurrence surveillance cohort, respectively. Furthermore, NMIBC patients were followed up with a median time of 20.5 months (range 0.03 to 24.03 months) to assess the predictive value of OncoUrine during recurrence monitoring.ResultsFor bladder cancer diagnosis, OncoUrine tested 47 samples and achieved a sensitivity/specificity/positive predictive value (PPV)/negative predictive value (NPV) of 80% (95% CI 44.2-96.5)/91.9% (95% CI 77.0-97.9)/72.7% (95% CI 39.3-92.7)/94.4% (95% CI 80.0-99.0) (kappa value 69.4%, 95% CI 44.4-94.3), indicating 72.3% of unnecessary cystoscopy. For recurrence diagnosis, OncoUrine tested 93 samples, and the sensitivity/specificity/PPV/NPV was 100% (95% CI 59.8-100.0)/68.2% (95% CI 57.1-77.7)/22.9% (95% CI 11.0-40.6)/100% (95% CI 92.3-100.0) (kappa value 27.0%, 95% CI 11.1-42.8), indicating 62.4% of spared cystoscopy. What is more, OncoUrine correctly predicted 80% (20/25) of final recurrence with 12/25 (48%) patients who were OncoUrine positive, but cystoscopy negative was followed with recurrence during follow-up. The test result of OncoUrine was also found significantly correlated with recurrence free survival (RFS) of NMIBC patients (median 34.4-month vs unreached; HR 6.0, 95% CI 2.7-13.5, P < 0.0001).ConclusionsOncoUrine showed potential value to reduce the frequency of unnecessary cystoscopy and the healthcare cost of bladder cancer patients. Patients with positive test results represented a population who were at high risk of recurrence and thus should be subject to frequent surveillance to ensure timely detection of any potential recurrence. This study has been registered in ClinicalTrials.gov with the number NCT04994197 posted on August 2021.

Dataset Information

Urinary expression of genes involved in DNA methylation and histone modification for diagnosis of bladder cancer in patients with asymptomatic microscopic haematuria.

Publications

Urinary expression of genes involved in DNA methylation and histone modification for diagnosis of bladder cancer in patients with asymptomatic microscopic haematuria.

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