Methylation Markers for Urine-Based Detection of Bladder Cancer: The Next Generation of Urinary Markers for Diagnosis and Surveillance of Bladder Cancer
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. 1. Introduction 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]. In approximately 70% of all cases the patients will present with nonmuscle invasive bladder cancer (NMIBC) of stages Ta, T1, or Tis, whereas the remaining 30% of the tumors will be muscle invasive stage T2–4 bladder cancers (MIBC). Tumor recurrences are frequent (70%) in patients with NMIBC, whereas progression to MIBC is less frequently observed (10%–30%) [5]. The standard treatment of NMIBC is transurethral resection (TUR) complemented by use of intravesical immunotherapy or chemotherapy in order to preclude recurrence and progression [6]. Risk factors associated with recurrence are tumor size, multiplicity, stage, and grade, whereas the risk factors for progression are tumor size, multiplicity, stage, high grade, and the presence of carcinoma in situ (CIS) [7]. The sensitivity of cystoscopy for NMIBC is close to 80% for white light cystoscopy and 96% when using hexaminolevulinate (HAL). The sensitivity of white light cystoscopy decreases to 48% and 68% for detection of dysplasia and CIS, respectively, whereas the sensitivity of cystoscopy using HAL for these lesions remains in the range of 93% to 95%
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