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.
Renard, Isabelle; Joniau, Steven; van Cleynenbreugel, Benet al.
[en] 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.
Research Center/Unit :
Service d'Urologie
Disciplines :
Oncology Urology & nephrology
Author, co-author :
Renard, Isabelle
Joniau, Steven
van Cleynenbreugel, Ben
Collette, Catherine
Naome, Chistophe
Vlassenbroeck, Ilse
Nicolas, Hubert
de Leval, Jean ; Université de Liège - ULiège > Département des sciences cliniques > Département des sciences cliniques
Straub, Joseph
Van Criekinge, W.
Hamida, Wissem
Hellel, Majed
Thomas, Alexandre ; Centre Hospitalier Universitaire de Liège - CHU > Urologie
De Leval, Laurence ; Centre Hospitalier Universitaire de Liège - CHU > Anatomie pathologique
Bierau, Katia
Waltregny, David ; Université de Liège - ULiège > Département des sciences cliniques > Urologie - GIGA-R : Labo de recherche sur les métastases
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.
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