title: FOXO1 down-regulation is associated with worse outcome in bladder cancer and adds significant prognostic information to p53 overexpression.
abstract: Nuclear FOXOs mediate cell cycle arrest and promote apoptosis. FOXOs and p53 could have similar effects as tumor suppressor genes. In spite of extensive literature, little is known about the role of FOXO1 and its relationship with p53 status in bladder cancer. Expression of FOXO1 and p53 were analyzed by immunohistochemistry in 162 urothelial carcinomas (UC). Decreased FOXO1 expression, p53 overexpression and the combination FOXO1 down-regulation/p53 overexpression were strongly associated with high grade (P=.030; P=.017; P=.004, respectively), high stage (P=.0001; P<.0001; P<.0001, respectively) or both (P=.0004; P<.0001; P<.0001, respectively). In the overall series of cases, p53 overexpression was associated with tumor progression (hazard ratio [HR]=3.18, 95% confidence interval [CI] 1.19-8.48, P=.02), but this association was even stronger if having any alteration in any of the 2 genes was considered (HR=3.51, 95% CI 1.34-9.21, P=.01). Having both FOXO1 down-regulation and p53 overexpression was associated with disease recurrence (HR=2.75, 95% CI 1.06-7.13, P=.03). In the analysis of the different subgroups, having any alteration in any of the 2 genes was associated with progression in low-grade (P=.005) and pTa (P=.006) tumors. Finally, the combined FOXO1 down-regulation/p53 overexpression was associated with disease recurrence specifically in high-grade (P=.04) and in pT1 stage tumors (P=.007). Adding FOXO1 expression to the immunohistochemical analysis of p53 can provide relevant prognostic information on progression and recurrence of bladder cancer. It may be particularly informative on the risk of progression in the more indolent and on the risk of recurrence in the more aggressive tumors.
authors.affiliation: Department of Pathology, Hospital del Mar, Barcelona 08003, Spain; Department of Health and Experimental Sciences, Universitat Pompeu Fabra, Barcelona 08003, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Lloreta
authors.affiliation: Dana Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Alba
authors.initials: A
authors.lastname: Font-Tello
authors.affiliation: Department of Pathology, Hospital del Mar, Barcelona 08003, Spain; Department of Health and Experimental Sciences, Universitat Pompeu Fabra, Barcelona 08003, Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Juanpere
authors.affiliation: Department of Urology, Hospital del Mar, Barcelona 08003, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Frances
authors.affiliation: Department of Pathology, Hospital del Mar, Barcelona 08003, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Lorenzo
authors.affiliation: Microarray Analysis Service, Hospital del Mar-IMIM Medical Research Institute, Barcelona 08003, Spain.
authors.forename: Lara
authors.initials: L
authors.lastname: Nonell
authors.affiliation: Department of Health and Experimental Sciences, Universitat Pompeu Fabra, Barcelona 08003, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: de Muga
authors.affiliation: Department of Pathology, Hospital del Mar, Barcelona 08003, Spain.
authors.forename: Ivonne
authors.initials: I
authors.lastname: Vázquez
authors.affiliation: Department of Urology, Hospital del Mar, Barcelona 08003, Spain.
authors.forename: Lluís
authors.initials: L
authors.lastname: Cecchini
authors.affiliation: Department of Health and Experimental Sciences, Universitat Pompeu Fabra, Barcelona 08003, Spain. Electronic address: silvia.hernandez@upf.edu.
authors.forename: Silvia
authors.initials: S
authors.lastname: Hernández-Llodrà
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D001706:Biopsy; D002277:Carcinoma / Q000737:chemistry* / Q000473:pathology / Q000628:therapy; D015536:Down-Regulation; D005260:Female; D000071161:Forkhead Box Protein O1 / Q000032:analysis*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D012307:Risk Factors; D046888:Tissue Array Analysis; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000032:analysis*; D015854:Up-Regulation; D001749:Urinary Bladder Neoplasms / Q000737:chemistry* / Q000473:pathology / Q000628:therapy; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
keywords: Bladder Cancer; FOXO1; Progression; Recurrence; p53