Currently, the gold standard for bladder cancer detection remains to be cystoscopy followed by histological examination for making the initial diagnosis and monitoring progression of bladder tumors. Although this approach provides valuable prognostic information regarding tumor status, it involves an invasive procedure that causes considerable discomfort to the patients which shows insufficient power to predict precisely the patient outcome and 10–40% of malignancies may be undetected. Because of the risk of recurrence, bladder cancer is a disease that requires life-long surveillance with periodic cystoscopy. Alternatively, urine cytology which has been used for decades is the standard noninvasive method for cancer detection. But the sensitivity of cytology is specifically insufficient for the detection of low stage and grade bladder tumors, whereby its accuracy is influenced by the pathologist’s experience.
An array of urine markers have been identified to improve the diagnostic ability of urine cytology and, perhaps, reduce the number of cystoscopies, consequently improving patient quality of life and patient care. In view of this, there is a dire need to identify prognostic biomarkers that can serve as reliable indicators of disease and predict recurrence more accurately. Over the past two decades a number of biomarkers have been identified and approved by FDA for screening of bladder cancers but initial enthusiasm for their clinical utility waned quickly because of lacked specificity, reproducibility as well as sensitivity, especially for low grade and stage of bladder cancer3. Hence the clinical applicability of these markers remains limited. Therefore, a more sensitive and noninvasive method is imperative for efficient BC detection.
Epigenetic changes are defined as changes in gene expression that are heritable through cell division, without associated DNA sequence alterations. DNA methylation occurs in distinct regions of promoters where cytosine residues located at the 5’ position of guanines in CpG dinucleotides which is not randomly distributed but is especially important in CpG-rich areas found in over 60% of the human genes, also called CpG islands. Hypermethylation of promoter CpG islands and somatic mutations are among the most common and specific types of genome alterations in human cancer and represent causative events in tumor development. Promoter hypermethylation negatively influences transcription and mutations may lead to activation of proto-oncogenes or inactivation of tumor suppressor genes.
Some epigenetic alterations occur early during tumorigenesis has been intensively investigated over the last ten years4,5, and could be used as targets for the molecular diagnosis of neoplastic cells in clinical specimens such as biological fluids that are readily accessible. Aberrant DNA promoter hypermethylation has been described in bladder cancer and have shown promising results. It seems to be an early event in the development of a number of solid tumors including bladder cancer6,7 and can thus be regarded as an early sign of cancer before the disease becomes muscle-invasive. The CpG methylation in BC has been reported to occur frequently in bladder cancer and to be associated with age, smoking status, gender, tumor location, stage, recurrence rate and progression8–12. In addition to detection of methylation in tumor tissue, analysis of gene methylation has been shown to be feasible from body fluids, including voided urine of patients with BC and appears to be more sensitive than urine cytology.
In bladder cancer, a large number of genes have been shown to harbor promoter hypermethylation, including Adenomatous Polyposis Coli (APC) as one of the most consistent and frequent targets. Expression and function of APC is known to be impacted either by physical changes in the sequence of DNA or by unprogrammed DNA methylation13,14. It is isolated and mapped at chromosomal band 5q2115,16. Loss of APC function results in nuclear accumulation of β-catenin, which acts as a transcriptional activator, ultimately leading to loss of cellular growth control17,18. Many studies have reported a high methylation frequency of APC promoter region in bladder cancer19–21. And DNA hypermethylation at the APC promoter correlated with cancer specific mortality following radical cystectomy.
Meta-analysis was used to evaluate the association between APC methylation and malignant tumors of bladder cancer, and to provide clues for further exploring its pathogenic effects and pathways in these diseases.