Abstract
Abstract Aims and background: The search for sensitive and specific progression and recurrence markers in bladder cancer is a major focus of many urological research groups. The aim of this study was to identify biomarkers on chromosome 8p in papillary urothelial carcinoma that give evidence for progression from non-invasive pTa to invasive pT1 stage. Candidate genes should be analyzed functionally in cell lines and validated immunohistochemically using tissue micro arrays. Material and methods: To find new progression markers 19 papillary urothelial carcinomas (9 pTa and 10 pT1) were investigated with array comparative genomic hybridization (aCGH) on Affymetrix Genome-Wide Human SNP Array 6.0. Therefore, tumor slides were manually microdissected, genomic DNA was isolated and DNA was hybridized on Affymetrix Chip together with reference DNA from 167 tumor-free patients. Computational analysis was performed with free Software “Genotyping-Console” from Affymetrix. MTUS1 gene and protein expression were investigated in bladder cancer cell lines and tumor tissue using qRT-PCR, Western blot and immunohistochemistry. Results: aCGH revealed more chromosomal aberrations overall as well as more deletions on chromosome 8p in pT1 tumors (50%) compared to pTa tumors (11%). Several putative progression-associated genes could be identified on 8p, for example SLC7A2, PDGFL, MTUS1, FGL1 and PCM1. MTUS1 (microtubule associated tumor suppressor 1) was chosen for further analysis, as in other tumor types this gene is known to be associated with frequent loss of heterozygosity at 8p22. However, to our knowledge, not much is known about its role in bladder cancer. Western blot analysis revealed expression of different isoforms in cell lines (140, 80 and 60 kDa) and tumor tissue (mainly 80kDa). Immunohistochemical staining of 128 papillary and 236 advanced tumors showed conflicting results compared to the aCGH findings. Conclusion: Whereas loss of genetic material at 8p22 harboring the MTUS1 gene is significantly associated with a pT1 stage in papillary urothelial carcinoma, pT1 tumors showed a significantly higher MTUS1 expression than pTa tumors as was shown by immunohistochemistry. At least in the pT1 group, expression loss contributed to worse overall survival, suggesting MTUS1 as a prognostic marker. Functional effects of MTUS1 overexpression will be analyzed in the future in RT112 cell line. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1164. doi:1538-7445.AM2012-1164
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