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Title: Identification and Validation of the Methylated TWIST1 and NID2 Genes through Real-Time Methylation-Specific Polymerase Chain Reaction Assays for the Noninvasive Detection of Primary Bladder Cancer in Urine Samples
Authors: Renard, Isabelle ×
Joniau, Steven
Van Cleynenbreugel, Ben
Collette, Catherine
Naômé, Christophe
Vlassenbroeck, Ilse
Nicolas, Hubert
de Leval, Jean
Straub, Josef
Van Criekinge, Wim
Hamida, Wissem
Hellel, Majed
Thomas, Alexandre
de Leval, Laurence
Bierau, Katja
Waltregny, David #
Issue Date: Jul-2010
Publisher: Elsevier Science
Series Title: European Urology vol:58 issue:1 pages:96-104
Abstract: BACKGROUND: Accumulating evidence suggests that DNA methylation markers could serve as sensitive and specific cancer biomarkers.
OBJECTIVE: To determine whether a panel of methylated genes would have the potential to identify primary bladder cancer (BCa) in voided urine samples.
DESIGN, SETTING, AND PARTICIPANTS: A pharmacologic unmasking reexpression analysis in BCa cell lines was initially undertaken to unveil candidate methylated genes, which were then evaluated in methylation-specific polymerase chain reaction (MSP) assays performed on DNA extracted from noncancerous and cancerous bladder tissues. The most frequently methylated genes in cancerous tissues, with 100% specificity, were retained for subsequent MSP analysis in DNA extracted from urine samples to build and validate a panel of potential methylated gene markers. Urine samples were prospectively collected at three urologic centres from patients with histologically proven BCa and processed for use in real-time MSP and cytologic analysis. Patients with nonmalignant urologic disorders were included as controls.
MEASUREMENTS: A urine sample was classified as valid when >/=10 copies of the gene encoding ss-actin were measured in the urine sediment genomic DNA. Sensitivity, specificity, and predictive values of the MSP and cytology tests were assessed and compared.
RESULTS AND LIMITATIONS: MSP assays performed on 466 of the 496 (94%) valid urine samples identified two genes, TWIST1 and NID2, that were frequently methylated in urine samples collected from BCa patients, including those with early-stage and low-grade disease. The sensitivity of this two-gene panel (90%) was significantly better than that of cytology (48%), with comparable specificity (93% and 96%, respectively). The positive predictive value and negative predictive value of the two-gene panel was 86% and 95%, respectively. CONCLUSIONS: Detection of the methylated TWIST1 and NID2 genes in urine sediments using MSP provides a highly (>/=90%) sensitive and specific, noninvasive approach for detecting primary BCa.
TRIAL REGISTRATION: BlCa-001 study - EudraCt 2006-003303-40.
ISSN: 0302-2838
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Urology Section (-)
× corresponding author
# (joint) last author

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