title: Overexpression of p53 in prostate carcinoma is associated with improved overall survival but not predictive of response to radiotherapy.
abstract: p53 gene mutations are among the most common specific genetic alterations in human cancer. Inactivation of p53 and subsequent protein accumulation has been implicated in a variety of human malignancies and associated with prostate cancer progression. In this study, we assessed p53 protein overexpression and gene mutations in prostate carcinoma and investigated associations between p53 alterations and clinicopathological parameters, survival, and response to radiotherapy. We evaluated 58 archival formalin-fixed, paraffin-embedded prostate carcinomas to detect abnormal p53 nuclear protein accumulation using immunohistochemistry. p53 mutational status of tumor DNA was evaluated using polymerase chain reaction-single-strand conformation polymorphism analysis of exons 5-9 and confirmed by direct DNA sequencing. Univariate and multivariate statistical analysis was used to determine the association of p53 status with clinical characteristics and response to radiotherapy. Overexpression of p53 was detected in 42 (72%) of 58 primary prostate carcinomas, but was undetectable in 7 samples of benign prostatic hyperplasias or 5 samples of normal prostate tissue. p53 exon 5-9 mutations were detected in 8 (14%) of 58 patient specimens. p53 mutational status, but not overexpression, was associated with higher Gleason scores (p=0.0145). Neither p53 overexpression nor mutation was associated with clinical stage, biochemical disease-free probability, or predictive of response to radiotherapy. p53 protein accumulation was inversely associated with improved overall survival (p=0.0108). Our studies demonstrate that p53 protein accumulation is a frequent alteration in prostate cancer. The disparity between p53 protein overexpression and p53 exon 5-9 mutations suggests the possibility of mutations outside this region or stabilization of wild-type p53 by alternative mechanisms. In our patient population, p53 protein overexpression or mutational status was not predictive of outcome in patients treated with radiation therapy. Additional studies are needed to further evaluate the association between p53 protein overexpression and improved overall survival.
authors.affiliation: Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Virginia Prostate Center and Sentara Cancer Institute, Norfolk, VA 23507, USA.
authors.forename: L S
authors.initials: LS
authors.lastname: Incognito
authors.forename: L H
authors.initials: LH
authors.lastname: Cazares
authors.forename: P F
authors.initials: PF
authors.lastname: Schellhammer
authors.forename: D A
authors.initials: DA
authors.lastname: Kuban
authors.forename: E O
authors.initials: EO
authors.lastname: Van Dyk
authors.forename: R P
authors.initials: RP
authors.lastname: Moriarty
authors.forename: G L
authors.initials: GL
authors.lastname: Wright
authors.forename: K D
authors.initials: KD
authors.lastname: Somers
mesh_terms: D000293:Adolescent; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009154:Mutation; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011237:Predictive Value of Tests; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology* / Q000532:radiotherapy; D016019:Survival Analysis; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D004273:DNA, Neoplasm; D016159:Tumor Suppressor Protein p53