title: Clinical significance of different types of p53 gene alteration in surgically treated prostate cancer.
abstract: Despite a multitude of p53 immunohistochemistry (IHC) studies, data on the combined effect of nuclear p53 protein accumulation and TP53 genomic inactivation are lacking for prostate cancer. A tissue microarray including 11,152 prostate cancer samples was analyzed by p53 IHC and fluorescence in situ hybridization. Nuclear p53 accumulation was found in 10.1% of patients including 1.4% with high-level and 8.7% with low-level immunostaining. TP53 sequencing revealed that 17 of 22 (77%) cases with high-level p53 immunostaining, but only 3% (1 of 31) low-level p53 cases carried putative dominant-negative mutations. TP53 deletions occurred in 14.8% of cancers. Both deletions and protein accumulation were linked to unfavorable tumor phenotype and prostate specific antigen (PSA) recurrence (p<0.0001 each). The combination of both methods revealed subgroups with remarkable differences in their clinical course. Tumors with either TP53 deletion (14%) or low-level p53 positivity (8.7%) had identical risks of PSA recurrence, which were markedly higher than in cancers without p53 alterations (p<0.0001). Tumors with both p53 deletion and low-level p53 positivity (1.5%) had a worse prognosis than patients with only one of these alterations (p<0.0001). Tumors with strong p53 immunostaining or homozygous inactivation through deletion of one allele and disrupting translocation involving the second allele had the worst outcome, independent from clinical and pathological parameters. These data demonstrate a differential clinical impact of various TP53 alterations in prostate cancer. Strong p53 immunostaining-most likely accompanying dominant negative or oncogenic p53 mutation-has independent prognostic relevance and may thus represent a clinical useful molecular feature of prostate cancer.
authors: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Martina
authors: M
authors: Kluth
authors: Silvia
authors: S
authors: Harasimowicz
authors: Lia
authors: L
authors: Burkhardt
authors: Katharina
authors: K
authors: Grupp
authors: Antje
authors: A
authors: Krohn
authors: Kristina
authors: K
authors: Prien
authors: Jovisa
authors: J
authors: Gjoni
authors: Thomas
authors: T
authors: Haß
authors: Rami
authors: R
authors: Galal
authors: Markus
authors: M
authors: Graefen
authors: Alexander
authors: A
authors: Haese
authors: Ronald
authors: R
authors: Simon
authors: Julia
authors: J
authors: Hühne-Simon
authors: Christina
authors: C
authors: Koop
authors: Jan
authors: J
authors: Korbel
authors: Joachim
authors: J
authors: Weischenfeld
authors: Hartwig
authors: H
authors: Huland
authors: Guido
authors: G
authors: Sauter
authors: Alexander
authors: A
authors: Quaas
authors: Waldemar
authors: W
authors: Wilczak
authors: Maria-Christina
authors: MC
authors: Tsourlakis
authors: Sarah
authors: S
authors: Minner
authors: Thorsten
authors: T
authors: Schlomm
mesh_terms: D002869:Chromosome Aberrations; D020868:Gene Silencing; D016158:Genes, p53; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D007610:Kallikreins / Q000378:metabolism; D008297:Male; D015999:Multivariate Analysis; D016016:Proportional Hazards Models; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000601:surgery; D046888:Tissue Array Analysis
chemical_list: C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen
keywords: mutation; p53; progression; prostate cancer; protein