| Abstract
| - BACKGROUND: We sought to identify and characterize potential alterations in E2F-1, atranscription factor that binds to the retinoblastoma protein (pRB), in bladder neoplasms and toelucidate a possible role for E2F-1 as an oncogene or a tumor suppressor gene. METHODS:Tumor samples from 133 evaluable patients with bladder cancer were analyzed for E2F-1 genemutations by use of polymerase chain reaction-single-strand conformational polymorphism(PCR-SSCP) analysis and DNA sequencing. In addition, tumors were studied for E2F-1 and pRBprotein expression by use of immunohistochemistry. Results from the above analyses werecorrelated with clinicopathologic parameters and outcome. All P values are two-sided.RESULTS: A polymorphism, consisting of a nucleotide change at amino acid codon 393 in exon7 (GGC→AGC [Gly→Ser]), was identified in seven of 133 case patients,being present in both tumor and corresponding normal tissues. No band-shifts were identified inthe nuclear-localization or DNA-binding domains on PCR-SSCP analysis. Onimmunohistochemical analysis, E2F-1 nuclear reactivity was observed in less than 5% ofthe cells from 53 tumors and in 5%-75% of the cells from the remaining 80 tumors.The pattern of E2F-1 protein expression was not altered in relation to the identifiedpolymorphism. pRB nuclear reactivity greater than 20% (of tumor cells stained) waspresent in 66% of the samples. E2F-1 nuclear reactivity correlated inversely with thepercentage of cells showing pRB reactivity (Kendall τb = −0.18; P = .019). On multivariate analysis, patients with lower E2F-1 reactivity hadstatistically significantly increased risks of progression to metastases (P = .001)and death (P = .02). CONCLUSIONS: E2F-1 alterations occur at the phenotypiclevel, rather than at the genotypic level, in bladder cancer. The adverse outcome for patientswhose tumors exhibit low E2F-1 nuclear expression suggests a possible tumor suppressor rolefor E2F-1 in bladder cancer.
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