Bladder Cancer-associated Protein, a Potential Prognostic Biomarker in Human Bladder Cancer*□S

Abstract

It is becoming increasingly clear that no single marker will have the sensitivity and specificity necessary to be used on its own for diagnosis/prognosis of tumors. Interpatient and intratumor heterogeneity provides overwhelming odds against the existence of such an ideal marker. With this in mind, our laboratory has been applying a long term systematic approach to identify multiple biomarkers that can be used for clinical purposes. As a result of these studies, we have identified and reported several candidate biomarker proteins that are deregulated in bladder cancer. Following the conceptual biomarker development phases proposed by the Early Detection Research Network, we have taken some of the most promising candidate proteins into postdiscovery validation studies, and here we report on the characterization of one such biomarker, the bladder cancer-associated protein (BLCAP), formerly termed Bc10. To characterize BLCAP protein expression and cellular localization patterns in benign bladder urothelium and urothelial carcinomas (UCs), we used two independent sets of samples from different patient cohorts: a reference set consisting of 120 bladder specimens (formalin-fixed as well as frozen biopsies) and a validation set consisting of 2,108 retrospectively collected UCs with long term clinical followup. We could categorize the UCs examined into four groups based on levels of expression and subcellular localization of BLCAP protein and showed that loss of BLCAP expression is associated with tumor progression. The results indicated that increased expression of this protein confers an adverse patient outcome, suggesting that categorization of staining patterns for this protein may have prognostic value. Finally, we applied a combinatorial two-marker discriminator using BLCAP and adipocyte-type fatty acid-binding protein, another UC biomarker previously reported by us, and found that the combination of the two markers correlated more closely with grade and/or stage of disease than the individual markers. The implications of these results in biomarker discovery are discussed. Molecular & Cellular Proteomics 9:161–177, 2010. Bladder cancer is the ninth most common cause of cancer worldwide for both sexes combined and the second most common malignancy of the genitourinary tract. Bladder neoplasias account for about 5% of all diagnosed cancers, affecting one in 4,000 people. An estimated 357,000 bladder cancer cases occurred in 2002 with more than 145,000 deaths reported in the same year (1). Malignancy of the urinary bladder comprises a large variety of histologically heterogeneous tumor types arising predominantly in the epithelial lining of the urinary bladder (urothelium) and the ureters. Tumor types of the urothelium include urothelial carcinomas (UCs), squamous cell carcinomas, and adenocarcinomas as well as other less frequent lesions (2). UCs account for more than 90% of bladder carcinomas and comprise a wide spectrum of lesions ranging in clinical severity from superficial bladder cancer to muscle-invasive and metastatic disease with the latter having a poor prognosis. Clinical management of the superficial form of the disease is currently done by endoscopic resection of the tumor supplemented with instillations of cytotoxic/cytostatic agents. Although intravesical instillations are widely used to avoid recurrences and even progression, up to 80% of patients with superficial bladder cancer lesions will recur, and of these, 25% will progress to invasive disease (3). Current prognostic parameters such as grade and stage, multifocality of carcinomas, and lymph node status cannot predict with certainty the long term outcome of bladder cancer, and as a result, there is a pressing need to identify markers that may be associated with bladder cancer progression and predict tumor behavior. For the past years, our laboratory has carried out a systematic and comprehensive effort to identify protein markers that

Cite this paper

@inproceedings{Moreira2010BladderCP, title={Bladder Cancer-associated Protein, a Potential Prognostic Biomarker in Human Bladder Cancer*□S}, author={Jos{\'e} Manuel Afonso Moreira and Gita Ohlsson and Pavel S Gromov and Ronald Simon and Guido Sauter and Julio E. Celis and Irina Gromova}, year={2010} }