Prognostic factors in stage T1 grade 3 bladder cancer survival: the role of G1-S modulators (p53, p21Waf1, p27kip1, Cyclin D1, and Cyclin D3) and proliferation index (ki67-MIB1).
OBJECTIVE
To determine the prognostic value of a subset of regulators of the transition from G1-to-S phase of cell cycle in stage T1 grade 3 bladder cancers.


METHODS
Fifty-one such cases were investigated to determine the significance on patient's survival of p53, p21Waf1, p27Kip1, Cyclin D1, Cyclin D3, and ki67-MIB1 (proliferation index). The statistical analysis included Kaplan-Meier methodology with Log-rank test and Cox' proportional hazard analysis.


RESULTS
Tumor size (p=0.0034), and the labeling index of ki67-MIB1 (p=0.0034), p53 (p=0.0332), p27kip1 (p=0.0059) and Cyclin D1 (p=0.0103) were associated to disease-free survival. Progression-free survival was related to tumor size (p<0.0001), ki67 (p=0.0163), p53 (p=0.0041), p27kip1 (p=0.0161), Cyclin D1 (p<0.0001) and Cyclin D3 (p<0.0001). Patient's overall survival was associated to Cyclin D3 (p<0.0001), p53 (p=0.0017), p21Waf1 (p=0.0142), Cyclin D1 (p<0.0001), ki67-MIB1 (p=0.0450), and tumor size (p=0.0296). Down-regulation of p27kip1 and Cyclin D3 over-expression (disease-free), over-expression of p53, Cyclin D1 and Cyclin D3 (progression-free), and over-expression of Cyclin D3 (overall survival) were independent predictors by Cox's multivariate analysis. Down-regulation of p27kip1 (p<0.001, R.R. 0.997, 95%C.I. 0.995-0.999), and over-expression of Cyclin D1 (p<0.001, R.R. 1.009, 95%C.I. 1.004-1.014) and Cyclin D3 (p=0.005, R.R. 1.013, 95%C.I. 1.004-1.022) were the main independent predictors.


CONCLUSIONS
Down-regulation of p27kip1 and over-expression of Cyclin D1 and Cyclin D3 might be relevant predictors of survival in stage T1 grade 3 bladder cancers, thus selecting a group of patients at higher risk of malignant behavior.
Lopez-Beltran
A
A
Department of Pathology, Reina Sofia University Hospital and Cordoba University Medical School, Cordoba, Spain. em1lobea@uco.es
Luque
R J
RJ
Alvarez-Kindelan
J
J
Quintero
A
A
Merlo
F
F
Carrasco
J C
JC
Requena
M J
MJ
Montironi
R
R
D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D000368:Aged; D000369:Aged, 80 and over; D001500:BCG Vaccine / Q000627:therapeutic use; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000502:physiology; D002455:Cell Division; D019938:Cyclin D1 / Q000502:physiology; D056743:Cyclin D3; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000502:physiology; D005260:Female; D016158:Genes, p53 / Q000502:physiology; D006801:Humans; D019394:Ki-67 Antigen / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D011379:Prognosis; D015996:Survival Rate; D025521:Tumor Suppressor Proteins / Q000502:physiology; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000401:mortality* / Q000473:pathology
D000276:Adjuvants, Immunologic; D001500:BCG Vaccine; C534696:CCND3 protein, human; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D056743:Cyclin D3; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D019394:Ki-67 Antigen; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27