Methylation of a Novel Panel of Tumor Suppressor Genes in Urine Moves Forward Non-Invasive Diagnosis and Prognosis in Bladder Cancer: A Two Center Prospective Study

 

 

Abstract 

Purpose

Changes in DNA methylation of tumor suppressor genes (TSGs) occurring early in carcinogenesis, represent potential indicators for cancer detection and disease evolution. Our aim was to examine the diagnostic, stratification and prognostic biomarker role of urinary methylation of a novel panel of TSGs in bladder cancer.

 

Material and Methods

Methylation of 18 TSGs was evaluated in two prospective independent sets of urinary samples (training, n=120; and validation, n=128) from bladder cancer patients (n=170) and controls (n=78) using methylation-specific multiplex ligation-dependent probe amplification assays (MS-MLPA). Diagnostic performance was evaluated using Receiver Operating Curves. Recurrence, progression, and disease-specific survival were analyzed using univariate and multivariate Cox models.

 

Results

PRDM2, HLTF, ID4, DLC1, BNIP3, H2AFX, CACNA1G, TGIF, and CACNA1A were discovered methylated in bladder cancer. CCND2, SCGB3A1, BNIP3, ID4 and RUNX3 were the most frequently methylated TSGs in both urinary sets. Methylation of several TSGs correlated to clinico-pathologic variables such as stage, tumor grade, focality or age. ROC analyses revealed significant diagnostic accuracies for RUNX3 and CACNA1A in the training set and for RUNX3 and ID4 in the validation set. Using univariate and multivariate analyses, CACNA1A methylation correlated to recurrence in the training set, while in the validation set, PRDM2 significantly associated with recurrence and BNIP3 with disease-specific survival, respectively.

 

Conclusions

TSGs methylation allowed histopathologic and clinical stratification. Urinary methylation offered non-invasive utility not only for diagnostic assessment but also as independent prognosticators in bladder cancer.

 

 

 

http://www.jurology.com/article/S0022-5347(13)00346-7/abstract