Research Article: Methylation Markers for Urine-Based Detection of Bladder Cancer: The Next Generation of Urinary Markers for Diagnosis and Surveillance of Bladder Cancer

Date Published: June 18, 2012

Publisher: Hindawi Publishing Corporation

Author(s): Thomas Reinert.


Cancer of the urinary bladder is the fifth most common neoplasm in the industrialized countries. Diagnosis and surveillance are dependent on invasive evaluation with cystoscopy and to some degree cytology as an adjunct analysis. Nomuscle invasive bladder cancer is characterized by frequent recurrences after resection, and up to 30% will develop an aggressive phenotype. The journey towards a noninvasive test for diagnosing bladder cancer, in order to replace or extend time between cystoscopy, has been ongoing for more than a decade. However, only a handful of tests that aid in clinical decision making are commercially available. Recent reports of DNA methylation in urine specimens highlight a possible clinical use of this marker type, as high sensitivities and specificities have been shown. This paper will focus on the currently available markers NMP22, ImmunoCyt, and UroVysion as well as novel DNA methylation markers for diagnosis and surveillance of bladder cancer.

Partial Text

Cancer of the urinary bladder is the fifth most common neoplasm in the industrialized countries and in the Unites States, with an estimated 70,530 new cases of bladder cancer diagnosed and with 14,680 deaths in 2010 [1]. Risk factors associated with the development of bladder cancer are mainly smoking and to a lesser extent workplace exposure to carcinogens [2, 3]. No genomic risk markers have been discovered apart from a few SNPs with a very low increase in relative risk [4].

Urinary cytology is the gold standard for noninvasive urinary diagnosis of bladder cancer, and the cytological examination is performed by a pathologist or cytologist who identifies cancer cells in the urine. The cells in the urine are classified into one of four categories: normal, atypical/indeterminate, suspicious, or malignant [13]. Urinary infections or other inflammatory conditions of the bladder may produce false positive results, and in addition the inter- and intraobserver variability of cytology are both high [14, 15]. Cytology has an overall test sensitivity of 44% (38–51, 95% CI) (Table 1), but low-grade tumors (grades I and II) have a lower test sensitivity than high-grade tumors. The test sensitivity of low-grade tumors is 27%, with a range from 0% to 93%, whereas high-grade tumors have a test sensitivity of 69%, with a range from 0% to 100%. Pooled estimates from 36 studies including 14,260 patients have established that the specificity of cytology is very high 96% (94–98; 95% CI) with a low false-positive interpretation [12]. In patients with a history of NMIBC the sensitivity is 38% (12–47; range) and the specificity is 94% (83–97; range) (Table 2) [12].

Presently, there are several investigational urinary biomarkers of bladder cancer which are not yet commercially available, but the most promising will perhaps be approved as urinary markers in the future. A noteworthy group of these promising emerging markers is DNA methylation markers. These markers have some advantages that make them promising as tumor markers: (i) the DNA is quite stable; (ii) methylation can be detected by sensitive real-time PCR assays in a high through-put manner; (iii) results are not dependent on subjective analysis. The remainder of this paper will focus on DNA methylation markers and their application for diagnosis and surveillance in bladder cancer.

Early diagnosis of bladder cancer, and careful followup for detection of recurrences after initial treatment, are main tasks of current urological research. The high rate of recurrences and the prolonged followup by cystoscopy and cytology make bladder cancer the most expensive cancer to treat, overall. However, by utilizing noninvasive urinary markers, it may be possible to improve the diagnosis of new cancers as well as improve the management of NMIBC. NMP22, UroVysion, and ImmunoCyt are well-examined urinary markers. NMP22 and UroVysion are both FDA-approved tests for initial diagnosis of bladder cancer in patients with a suspicion of bladder cancer and for surveillance of bladder cancer; however, ImmunoCyt is only approved for the surveillance of bladder cancer in conjunction with urinary cytology and cystoscopy. All three markers have a higher sensitivity than cytology, but a lower specificity (Table 1). Furthermore, the specificity of NMP22 and ImmunoCyt are influenced by urinary conditions other than bladder cancer, which makes them unusable in many situations (Table 1).

Detecting bladder cancer using diagnostic or surveillance markers remains a challenge, as none of the currently approved markers can replace cystoscopy or prolong the time between cystoscopies. The field of methylation biomarkers is promising, but requires more prospective multicenter studies that explicitly clarify the purpose of the study as screening, diagnosis of primary disease, or surveillance. In addition, these studies should include the appropriate patients in order to validate the current findings in an unbiased manner. Currently, at least one such study combining methylation markers and FGFR3 mutational markers for surveillance of bladder cancer is ongoing (UROMOL, FP7 EU study). This study investigates urine samples from more than 1200 patients with bladder cancer in several clinical centers in Europe.




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