Novel Urine-Based DNA Methylation Biomarkers for Urothelial Bladder Carcinoma Detection in Patients With Hematuria

NCT ID: NCT05362539

Last Updated: 2022-05-05

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 246 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-02-01
• Study Completion Date: 2022-04-01

Brief Summary

The current study aimed to assess the diagnostic performance of novel urine-based DNA hypermethylation of six genes (GATA4, P16, P14, APC, CDH1 and CD99) for UBC detection in patients with hematuria.

Detailed Description

According to GLOBOCAN data, bladder cancer (BC) is considered a major health problem that represents 3% of all cancer diagnoses. Urothelial bladder carcinoma (UBC) accounts for the vast majority (>90%) of BC cases with predominance of non-muscle invasive disease (Ta, Tis or T1) in 75% of patients while others show muscle invasion (T2-4).

In refereed population, UBC is usually diagnosed as a result of work-up for hematuria at a rate of 2-5% following an evaluation of asymptomatic microscopic hematuria, and, up to 5-15% of patients with macroscopic hematuria. Therefore, a timely prompt evaluation of hematuria can give to earlier diagnosis and better survival of UBC.

Currently, cystoscopy /cross sectional imaging are the gold standard tools for UBC diagnosis in patients with hematuria. Unfortunately, these costly, invasive and painful diagnostics could miss early, small/flat bladder lesions. Urine cytology has been proposed as a non-invasive alternative test with high specificity, however, it lacks sensitivity for diagnosis of low grade (LG) tumors.

Over the last decades, multiple researches have output different markers for UBC diagnosis. Based on their target of assessment, these markers include screening for soluble antigens (BTA-Stat, NMP-22, surviving, etc.), cell surface antigens (Cytokeratins and UroVysion), genomic markers (Cxbladder and Xpert) and urinary metabolomics (CRAT and SLC25A20). However, most of these markers are limited by unsatisfying diagnostic performance, high cost or lack of validation.

Several preliminary studies have shown that DNA methylation, a critical step in transcription regulation, is chemically stable and can be precisely quantified, making it an attractive marker for UBC detection. Both local and global DNA hypermethylation in BC specimens are usually associated with inactivation of tumor suppressor genes. These methylations changes could be effectively identified in urine sediments as well as tumor tissues.

In the current literature, multiple studies investigated the performance of DNA hypermethylation of either individual or panel genes with reported sensitivity (SN) and specificity (SP) values that range from 40-95 % and 10-100 %, respectively. Most of these studies were limited by tumor characteristics heterogeneity (majority were ≥T2 and high grade (HG) disease; which did not reflect the daily practice, inclusion of different BC histological variants), lack of external validation and small sample size.

The aim of our study is to assess the diagnostic performance of novel urine-based DNA methylation six genes (GATA4, P16, P14, APC, CDH1 and CD99) for UBC detection in patients with hematuria. Moreover, we investigated the methylation pattern of these genes in different stages and grades of UBC.

Conditions

Bladder Cancer

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: DIAGNOSTIC
• Blinding Strategy: NONE

Study Groups

Hematuria patients

Voided urine was collected from consecutive patients presented with hematuria at our institute for urine cytology and DNA hypermethylation assay of the assigned genes using methylation-specific Polymerase Chain Reaction (PCR). Further assessment by office cystoscopy and imaging with subsequent inpatient cystoscopic biopsy for positive findings, was done. The diagnostic characteristics of DNA hypermethylation and urine cytology were assessed based on its capability to predict UBC noninvasively

Group Type: EXPERIMENTAL

Cystoscopy

Intervention Type: PROCEDURE

diagnostic cystoscopy for detection of any bladder lesions

Computed tomography

Intervention Type: DIAGNOSTIC_TEST

Computed tomography for patients to exclude bladder lesions

DNA hypermethylation assay

Intervention Type: GENETIC

DNA hypermethylation assay of six genes (GATA4, P16, P14, APC, CDH1 and CD99)

Urine cytology

Intervention Type: DIAGNOSTIC_TEST

voided urine cytology for all patients

Interventions

Cystoscopy

diagnostic cystoscopy for detection of any bladder lesions

Intervention Type: PROCEDURE

Computed tomography

Computed tomography for patients to exclude bladder lesions

Intervention Type: DIAGNOSTIC_TEST

DNA hypermethylation assay

DNA hypermethylation assay of six genes (GATA4, P16, P14, APC, CDH1 and CD99)

Intervention Type: GENETIC

Urine cytology

voided urine cytology for all patients

Intervention Type: DIAGNOSTIC_TEST

Eligibility Criteria

Inclusion Criteria

• patients with hematuria (macroscopic or microscopic)

Exclusion Criteria

• history of Bladder Cancer
• history of pelvic irradiation,
• bleeding diathesis or receiving anticoagulants
• patients with upper urinary tract neoplasm or urolithiasis

• Minimum Eligible Age: 18 Years
• Accepts Healthy Volunteers: No

Sponsors

Mansoura University

OTHER

Sponsor Role: lead

Responsible Party

Amr Abdel-Lateif El-Sawy

Lecturer of Urology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Amr A Elsawy

Role: PRINCIPAL_INVESTIGATOR

Mansoura University

Locations

Mansoura Urology and Nephrology Center

Al Mansurah, DK, Egypt

Countries

Egypt

Other Identifiers

AS-4-2022

Identifier Type: -

Identifier Source: org_study_id