© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 10, 874-881,
May 19, 1999
© 1999 Oxford University Press
REPORTS |
Prognostic Significance of Transcription Factor E2F-1 in Bladder Cancer: Genotypic and Phenotypic Characterization
Affiliations of authors: F. Rabbani, G. Dalbagni (Urology Service, Department of Surgery), V. M. Richon (Cell Biology Program), I. Orlow, M.-L. Lu, M. Drobnjak, M. Dudas, E. Charytonowicz, C. Cordon-Cardo (Department of Pathology), Memorial Sloan-Kettering Cancer Center, New York, NY.
Correspondence to: Carlos Cordon-Cardo, M.D., Ph.D., Division of Molecular Pathology, Memorial Sloan-Kettering Cancer Center, Rm. S-801, 1275 York Ave., New York, NY 10021 (e-mail: cordon-c{at}mskcc.org).
BACKGROUND: We sought to identify and characterize potential alterations in E2F-1, a
transcription factor that binds to the retinoblastoma protein (pRB), in bladder neoplasms and to
elucidate 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 gene
mutations 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 pRB
protein expression by use of immunohistochemistry. Results from the above analyses were
correlated 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 exon
7 (GGC
AGC [GlySer]), was identified in seven of 133 case patients,
being present in both tumor and corresponding normal tissues. No band-shifts were identified in
the nuclear-localization or DNA-binding domains on PCR-SSCP analysis. On
immunohistochemical analysis, E2F-1 nuclear reactivity was observed in less than 5% of
the 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 identified
polymorphism. pRB nuclear reactivity greater than 20% (of tumor cells stained) was
present in 66% of the samples. E2F-1 nuclear reactivity correlated inversely with the
percentage of cells showing pRB reactivity (Kendall 
b = -0.18; P = .019). On multivariate analysis, patients with lower E2F-1 reactivity had
statistically significantly increased risks of progression to metastases (P = .001)
and death (P = .02). CONCLUSIONS: E2F-1 alterations occur at the phenotypic
level, rather than at the genotypic level, in bladder cancer. The adverse outcome for patients
whose tumors exhibit low E2F-1 nuclear expression suggests a possible tumor suppressor role
for E2F-1 in bladder cancer.
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