p53, p21, pRB, and p16 expression predict clinical outcome in cystectomy with bladder cancer.
OBJECTIVE
To determine whether p53, p21, pRB, and/or p16 expression is associated with bladder cancer stage, progression, and prognosis.


METHODS
Immunohistochemical staining for p53, p21, pRB, and p16 was carried out on serial sections from archival specimens of 80 patients who underwent bilateral pelvic lymphadenectomy and radical cystectomy for bladder cancer (median follow-up, 101 months).


RESULTS
p53, p21, and pRB or p16 expression was altered in 45 (56%), 39 (49%), and 43 (54%) tumors, respectively. Sixty-six patients (83%) had at least one marker altered, and 21 patients (26%) had all three altered. Abnormal expressions of p53, p21, and pRB/p16 expression were associated with muscle-invasive disease (P=.007, P=.003, and P=.003, respectively). The alteration of each marker was independently associated with disease progression (P< or =.038) and disease-specific survival (P< or =.039). In multivariable models that included standard pathologic features and p53 with p21 or p53 with pRB/p16, only p53 and lymph node metastases were associated with bladder cancer progression (P< or =.026) and death (P< or =.028). In models that included p21 and pRB/p16, only p21 and lymph node metastases were associated with bladder cancer progression (P< or =.022) and death (P< or =.028). In a model that included the combined variables p53/p21 and pRB/p16, only p53/p21 and lymph node status were associated with bladder cancer progression (P< or =.047) and death (P< or =.036). The incremental number of altered markers was independently associated with an increased risk of bladder cancer progression (P=.005) and mortality (P=.007).


CONCLUSIONS
Although altered expression of each of the four cell cycle regulators is associated with bladder cancer outcome in patients undergoing radical cystectomy, p53 is the strongest predictor, followed by p21, suggesting a more pivotal role of the p53/p21 pathway in bladder cancer progression.
Scott Department of Urology, Baylor College of Medicine, 6560 Fannin, Suite 2100, Houston, TX 77030, USA.
Shahrokh F
SF
Shariat
Hideo
H
Tokunaga
JainHua
J
Zhou
JaHong
J
Kim
Gustavo E
GE
Ayala
William F
WF
Benedict
Seth P
SP
Lerner
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002295:Carcinoma, Transitional Cell / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism*; D015653:Cystectomy; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016016:Proportional Hazards Models; D016160:Retinoblastoma Protein / Q000378:metabolism*; D015996:Survival Rate; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000601:surgery
D014408:Biomarkers, Tumor; C493956:CDKN1A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53