title: Loss of heterozygosity at 9q32-33 (DBC1 locus) in primary non-invasive papillary urothelial neoplasm of low malignant potential and low-grade urothelial carcinoma of the bladder and their associated normal urothelium.
abstract: Tumour recurrence has a major impact on patients with non-invasive papillary urothelial tumours of the bladder. To explore the role of DBC1 (deleted in bladder cancer 1 locus), a candidate tumour suppressor gene located at 9q32-33, as prognostic marker we have performed loss of heterozygosity (LOH) testing in 49 patients with primary papillary urothelial tumours and associated normal urothelium. Data from the 38 tumours and 11 specimens of normal urothelium that were informative in the LOH study (D9S195 marker) showed that LOH in urothelium (45.4%) but not in non-invasive tumours (60.5%) was associated with tumour recurrence (p = 0.026) but not to grade or progression. Also, tumours whose normal urothelium had LOH were larger (p = 0.020) and showed cyclin D1 over-expression (p = 0.032). Non-significant increased expression of p53, p21Waf1, apoptotic index and tumour proliferation, and decreased expression of p27Kip1 or cyclin D3 also characterized tumours whose normal urothelium had LOH. The expression of these G1-S modulators, apoptotic index and tumour proliferation was more heterogeneous in papillary urothelial tumours, irrespective of having retained heterozygosity or LOH. Also, Bax expression decreased in papillary urothelial tumours having LOH (p = 0.0473), but Bcl-2 was unrelated to LOH status. In addition, FGFR3 protein expression decreased in LOH tumours (p = 0.036) and in those having LOH in their normal urothelium (p = 0.022). FGFR3 immunohistochemical expression was validated by western blot in selected cases. The survival analysis selected LOH in normal urothelium as a marker of disease-free survival (log-rank 5.32, p = 0.021), progression-free survival (log-rank 3.97, p = 0.046) and overall survival (log-rank 4.26, p = 0.038); LOH in tumours was significant in progression-free survival (log-rank 3.83, p = 0.042). It is concluded that LOH at the DBC1 locus in normal urothelium seems to be relevant in the prognosis of non-invasive papillary tumours of the bladder via selecting cases with increased proliferation, frequent alterations of the G1-S phase modulators, and decreased FGFR3 protein expression.
authors.affiliation: Department of Pathology, Reina Sofia University Hospital and Cordoba University Medical School, Spain. em1lobea@uco.es
authors.forename: A
authors.initials: A
authors.lastname: Lopez-Beltran
authors.forename: J
authors.initials: J
authors.lastname: Alvarez-Kindelan
authors.forename: R J
authors.initials: RJ
authors.lastname: Luque
authors.forename: A
authors.initials: A
authors.lastname: Blanca
authors.forename: A
authors.initials: A
authors.lastname: Quintero
authors.forename: R
authors.initials: R
authors.lastname: Montironi
authors.forename: L
authors.initials: L
authors.lastname: Cheng
authors.forename: R
authors.initials: R
authors.lastname: Gonzalez-Campora
authors.forename: M J
authors.initials: MJ
authors.lastname: Requena
mesh_terms: D000368:Aged; D017209:Apoptosis / Q000235:genetics; D015415:Biomarkers / Q000032:analysis; D015153:Blotting, Western / Q000379:methods; D002295:Carcinoma, Transitional Cell / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D009419:Nerve Tissue Proteins; D016133:Polymerase Chain Reaction / Q000379:methods; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000032:analysis; D018709:Statistics, Nonparametric; D016019:Survival Analysis; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000235:genetics*; D019459:Urothelium / Q000378:metabolism
chemical_list: C112308:BRINP1 protein, human; D015415:Biomarkers; D018797:Cell Cycle Proteins; D009419:Nerve Tissue Proteins; D025521:Tumor Suppressor Proteins; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3