A panel of prognostic protein markers for progression in non-muscle invasive bladder cancer - a multicenter tissue microarray validation study

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Bladder cancer is the fifth most common cancer in the Western world. The histopathological parameters used in the clinic cannot precisely predict the individual disease course. Bladder cancer patients are therefore monitored thoroughly for disease recurrence and progression by urine and cystoscopy examinations. This is accompanied by large discomfort for the patients and heavy cost to society. Identification of prognostic molecular markers may enhance our ability to individualize treatment. We investigated the prognostic value of MCM7, ADAM10, TRIM29, Aurora Kinase B and Cyclin D1 in patients with stage Ta and T1 urothelial carcinomas. Transcripts from the five genes encoding these proteins were previously included in gene expression signatures for outcome prediction for non-muscle invasive bladder cancer (NMIBC). As a training-set, we used primary NMIBC tissue-microarray specimens from a Danish cohort of 283 patients with long-term follow-up. For validation of the results we used three independent patient cohorts with long-term follow-up from Sweden, Spain, and Taiwan. In total 649 primary NMIBC tissue-microarray specimens from patients with long-term follow-up were used. Protein expression was measured by immunohistochemistry and antibody specificity was validated by Western blotting. All cut-points were selected in the Danish patient cohort using ROC curves and then applied to the independent validation patient cohort. In the Danish patient cohort, we found the expression of MCM7, ADAM10, TRIM29, Aurora Kinase B, and Cyclin D1 to be significantly associated with progression to stage T2-4 bladder cancer (for each marker: log-rank test; p<0.001). Multivariate Cox regression analysis identified ADAM10 (p=0.002), TRIM29 (p=0.001), Aurora Kinase B (p<0,001) and Cyclin D1 (p=0.003) as independent prognostic markers. Furthermore, ADAM10, TRIM29, Aurora Kinase B, and Cyclin D1 expression significantly sub-grouped EORTC low risk patients. Similarly, TRIM29, Aurora Kinase B, and Cyclin D1 significantly sub-grouped EORTC high risk patients. We are currently validating the results in the independent NMIBC cohort with long-term follow-up. These results will be presented at AACR annual meeting 2012. We conclude that ADAM10, TRIM29, Aurora Kinase B, and Cyclin D1 may have prognostic value for guiding optimal treatment of NMIBC patients if successfully validated in the independent patient cohorts. Additional prospective studies are needed for further validation of the clinical relevance of the marker panel
Original languageEnglish
Publication year15 Apr 2012
Publication statusPublished - 15 Apr 2012

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