Abstract
BackgroundEpigenetic alterations are a hallmark of human cancer. In this study, we aimed to investigate whether aberrant DNA methylation of cancer-associated genes is related to urinary bladder cancer recurrence.MethodsA set of 4 genes, including CDH1 (E-cadherin), SFN (stratifin), RARB (retinoic acid receptor, beta) and RASSF1A (Ras association (RalGDS/AF-6) domain family 1), had their methylation patterns evaluated by MSP (Methylation-Specific Polymerase Chain Reaction) analysis in 49 fresh urinary bladder carcinoma tissues (including 14 cases paired with adjacent normal bladder epithelium, 3 squamous cell carcinomas and 2 adenocarcinomas) and 24 cell sediment samples from bladder washings of patients classified as cancer-free by cytological analysis (control group). A third set of samples included 39 archived tumor fragments and 23 matched washouts from 20 urinary bladder cancer patients in post-surgical monitoring. After genomic DNA isolation and sodium bisulfite modification, methylation patterns were determined and correlated with standard clinic-histopathological parameters.ResultsCDH1 and SFN genes were methylated at high frequencies in bladder cancer as well as in paired normal adjacent tissue and exfoliated cells from cancer-free patients. Although no statistically significant differences were found between RARB and RASSF1A methylation and the clinical and histopathological parameters in bladder cancer, a sensitivity of 95% and a specificity of 71% were observed for RARB methylation (Fisher's Exact test (p < 0.0001; OR = 48.89) and, 58% and 17% (p < 0.05; OR = 0.29) for RASSF1A gene, respectively, in relation to the control group.ConclusionIndistinct DNA hypermethylation of CDH1 and SFN genes between tumoral and normal urinary bladder samples suggests that these epigenetic features are not suitable biomarkers for urinary bladder cancer. However, RARB and RASSF1A gene methylation appears to be an initial event in urinary bladder carcinogenesis and should be considered as defining a panel of differentially methylated genes in this neoplasia in order to maximize the diagnostic coverage of epigenetic markers, especially in studies aiming at early recurrence detection.
Highlights
Epigenetic alterations are a hallmark of human cancer
Methylation-Specific Polymerase Chain Reaction (MSP) analysis was performed on 49 urothelial carcinoma (UC) obtained from unrelated patients, 14 of them matched with normal tissue samples, 3 squamous cell carcinomas and 2 adenocarcinomas
Compared to the results shown by the biopsy analysis of UCs, retinoic acid receptor (RARB) had a sensitivity of 95% and specificity of 71% by Fisher's Exact test (p < 0.0001; Odds Ratio (OR) = 48.89); for the same parameters, Ras association domain family 1 gene (RASSF1A) showed 58% and 17%, respectively (p < 0.05; OR = 0.29) (Table 4)
Summary
Epigenetic alterations are a hallmark of human cancer. In this study, we aimed to investigate whether aberrant DNA methylation of cancer-associated genes is related to urinary bladder cancer recurrence. Conventional diagnosis for urinary bladder cancer is based on morphological, histological and pathological features. These criteria provide essential prognostic information, but show insufficient power to precisely predict patient outcome. The use of genetic and epigenetic alterations for the early detection of bladder cancer is promising because it is believed that some molecular events occur at the beginning of the carcinogenesis process. Molecular diagnosis may allow detection before clinical or radiographic manifestations In this context, a sensitive and specific noninvasive test could prescreen patients with clinical symptoms as well as those at high risk, and would be useful in monitoring patients post-surgically for early detection of recurrence
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