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.

No mutations of FGFR3 in normal urothelium in the vicinity of urothelial carcinoma of the bladder harbouring activating FGFR3 mutations in patients with bladder cancer

“…9,12 Most recently, Lopez-Beltran et al could show that the deletion of the DBC1 (deleted in bladder cancer 1) locus on 9q32-33 in normal urothelium seemed to be frequent and influenced the prognosis of noninvasive papillary bladder cancer by selecting cases with an increased proliferation. 17 These findings of a frequent chromosomal alteration on chromosome 9q fit well with our own results from a LOH study on normal urothelium in cystectomy specimens showing the most frequent deletions in microsatellite marker D9S1113 located on chromosome 9q33.3-34.1 which is in close proximity to DBC1.…”

Progressive increase of genetic alteration in urinary bladder cancer by combined allelotyping analysis and comparative genomic hybridization

“…- (CGH) has to be performed. CGH results from our present study, and those of others, found that frequent chromosome losses are on 3p, 4p, 6q, 9p, 9q, 8p, 11p, 13q, 17p, and 18q while chromosomes gains are on 1q, 3q, 5p, 6p, 7p, 8q, 10q, 11q, 13q, 17q, 20q (12,19,20,(25)(26)(27)(28)(29)(30). As a result, the high frequency of allelic imbalance of chromosome 1q, 10q, and 11q, detected in this study was probably due to chromosomal gain.…”

Urothelial dysplasia and other flat lesions of the urinary bladder: clinicopathologic and molecular features

“…The third wave of genetic alterations occurs when the fully transformed phenotype of carcinoma in situ is apparent. Similarly, Lopez-Beltran et al [55] recently demonstrated MACC with LOH at 9q32-33 DBC1 (deleted in bladder cancer 1) in normal urothelium from patients with low-grade papillary urothelial tumors. The most striking observation in their study was the association between DBC1 locus in normal urothelium with tumor recurrence and progression [55].…”

“…Similarly, Lopez-Beltran et al [55] recently demonstrated MACC with LOH at 9q32-33 DBC1 (deleted in bladder cancer 1) in normal urothelium from patients with low-grade papillary urothelial tumors. The most striking observation in their study was the association between DBC1 locus in normal urothelium with tumor recurrence and progression [55]. Of the 38 lowgrade stage Ta papillary urothelial carcinomas and associated samples of 11 normal urothelium specimens, which were informative in their 9q32-33 LOH study, 12 (31.6%) showed tumor recurrence and 5 (13.1%) showed tumor stage progression when there was deletion of DBC1.…”