Cooperative effect of cell-cycle regulators expression on bladder cancer development and biologic aggressiveness

Abstract

The aim of this study was to evaluate the association between p53, p21, p27 and Rb expression, alone or in combination, with pathological features and clinical outcomes of urothelial carcinoma of the bladder. Immunohistochemical staining for p53, p21, p27 and pRB was performed on tissue microarrays comprising normal urothelium from nine controls, transurethral resection specimens from 74 patients with Ta, Tis and/or T1 bladder urothelial carcinoma, radical cystectomy specimens from 226 consecutive urothelial carcinoma patients, and lymph nodes with tumor invasion from 50 of the 226 cystectomy patients. All nine controls had normal status of biomarkers. The proportion of biomarkers alterations was highest in lymph node metastases. p53, pRB and p27 were associated with pathologic stage, lymphovascular invasion and lymph node metastases (P-valuesr0.050). Each biomarker alone, each combination of two biomarkers and the number of altered biomarkers were all independently associated with disease recurrence and bladder cancer-specific death (Pvaluesr0.046). In patients with organ-confined disease, p53, p21 and p27 were independently associated with disease recurrence and bladder cancer-specific death (P-valuesr0.046). There was a good but not perfect concordance in the expression of biomarkers between matched transurethral resection and cystectomy specimens (n ¼ 22; concordance rates: 77-86%) and between matched lymph node and cystectomy specimens (n ¼ 50, 70-92%). In conclusion, p53, p21, p27 and pRB have a cooperative/synergistic role in the biologic behavior of bladder urothelial carcinoma. In contrast to the use of single biological markers, evaluation of their combined status may improve prognostic models and help identify patients who might benefit from adjuvant therapies and in decision-making. Modern Pathology (2007) 20, 445-459.

Multiple biomarkers improve prediction of bladder cancer recurrence and mortality in patients undergoing cystectomy

“…We and others have previously shown that altered expressions of cyclin E1, p53, pRB, p21, and p27 are independent determinants of prognosis that can act cooperatively/synergistically to promote tumor progression. [19][20][21]24,27 In agreement with these findings, we found that patients with 3 or more altered biomarkers had a statistically and clinically significantly higher risk of disease recurrence or bladder cancer-specific mortality compared with patients with 0-2 altered biomarkers. The choice of the biomarkers was based on previous studies estab- lishing their independent prognostic value in traditional multivariable analyses.…”

“…The choice of the biomarkers was based on previous studies estab- lishing their independent prognostic value in traditional multivariable analyses. [15][16][17][18][19][20][21][22][23][24][25][26][27][28] Moreover, these biomarkers are commonly used in pathology departments and most pathologists are familiar with immunohistochemical staining and interpretation of these biomarkers. However, combinations of other biomarkers reflecting the functional status of different pathways/phenomena associated with bladder cancer progression may provide similar or even greater predictive accuracy.…”

“…Nuclear p53 immunoreactivity was considered altered when samples demonstrated at least 10% nuclear reactivity. [16][17][18]20,[25][26][27] p21 immunoreactivity was considered altered when samples demonstrated less than 10% staining. 19,20 pRB immunoreactivity was assigned to 1 of 3 categories of nuclear staining in the tumor cells: no nuclear reactivity; normal heterogeneous; and strong homogeneous (>50%).…”

“…Staining and scoring protocols for cyclin E1, p53, p21, pRB, and p27 were performed as described elsewhere. 20,24,27,30 Multiple positive and negative control sections were included in each run.…”

“…[15][16][17][18][19][20][21][22][23][24][25][26][27] Several studies have shown that accumulation of altered expression of several of these immunohistochemical markers adds important prognostic information in patients treated with radical cystectomy. [15][16][17][18][19][20][21][22][23][24][25][26][27][28] A clinical trial is under way testing whether alterations of p53 nuclear expression can be used prospectively to identify high-risk patients and whether there is a benefit to administering adjuvant methotrexate, vinblastine, doxorubicin (Adriamycin), and cisplatin (M-VAC) chemotherapy in p53-altered patients. 25,26,29 In the present study we hypothesized that the expression of a panel of established cell cycle regulators (ie, p53, pRB, p21, p27, and cyclin E1) could help identify patients with pTa-3 N0M0 UCB who are at increased risk for disease progression and therefore would be candidates for systemic adjuvant chemotherapy.…”