Cyclin D1 expression in papillary superficial bladder cancer: its association with other cell cycle-associated proteins, cell proliferation and clinical outcome.
Cyclin D1 contributes to regulate G1 progression by forming a complex with different cyclin-dependent kinases. It has oncogenic properties and is frequently overexpressed in several human tumor types. In our study, expression of cyclin D1 and Ki67, a proliferation marker, was evaluated by immunohistochemistry in human papillary superficial (pTa-pT1) bladder cancers and was correlated with p27(Kip1), p21(Waf1) and c-erbB-2 expression, with p53 gene status and protein expression, ploidy and cancer progression. Cyclin D1 expression was neither associated with tumor stage nor with tumor grade but high cyclin D1 expression (> or =25% positive nuclei) was significantly associated with p53 gene mutation (p = 0.012), low p21(Waf1) (p = 0.015) and high p27(Kip1) (p = 0.016) protein expression. Ki67 expression was not associated with tumor stage but a high proliferation index (> or =10% positive nuclei) was significantly associated with high tumor grade (p = 0.001) and with DNA aneuploidy (p = 0.005). There was no significant difference in proliferative activity between high and low cyclin D1 expressor tumors. Patients whose tumors showed high expression of cyclin D1 displayed a significantly longer disease-free survival (p < 0.001 by log-rank test). Increased Ki67 expression was significantly associated with shorter disease-free survival (p = 0.003). Both cyclin D1 (p = 0.027; RR = 1.898) and Ki67 (p = 0.047; RR = 1.932) protein expressions were independent predictors of reduced disease-free survival on a multivariate analysis that also included p27(Kip1) expression and tumor stage. The simultaneous presence of low cyclin D1, low p27(Kip1) and high Ki67 expression defined a "high-risk" group of patients who displayed a significantly increased risk of recurrence (p < 0.0001). These results suggest that evaluation of cell cycle-associated markers can help to identify high-risk patients and may affect the management of patients with papillary superficial bladder cancer.
Sgambato
Alessandro
A
Centro di Ricerche Oncologiche "Giovanni XXIII," Istituto di Patologia Generale, Catholic University, Rome, Italy. asgambato@rm.unicatt.it
Migaldi
Mario
M
Faraglia
Beatrice
B
De Aloysio
Graziella
G
Ferrari
Paolo
P
Ardito
Raffaele
R
De Gaetani
Carmela
C
Capelli
Giovanni
G
Cittadini
Achille
A
Trentini
Gian Paolo
GP
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000096:biosynthesis; D002291:Carcinoma, Papillary / Q000378:metabolism* / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000096:biosynthesis*; D002455:Cell Division; D015331:Cohort Studies; D019938:Cyclin D1 / Q000096:biosynthesis; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000096:biosynthesis*; D008297:Male; D008875:Middle Aged; D011003:Ploidies; D011237:Predictive Value of Tests; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis; D018570:Risk Assessment; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000473:pathology*
D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D019394:Ki-67 Antigen; D018719:Erb-b2 Receptor Tyrosine Kinases; D025521:Tumor Suppressor Proteins