Prognostic role of cell cycle–related biomarkers in clear cell renal cell carcinoma.

Abstract

404 Background: Cell cycle regulatory molecules are implicated in various stages of carcinogenesis. In this study we systematically evaluate the impact of aberrant expression of cell cycle regulators on oncological outcomes in clear cell renal carcinoma (ccRCC). Methods: After obtaining IRB approval, immunohistochemistry for Cyclin D, Cyclin E, p16, p21, p27, p53, p57, and Ki-67 was performed on tissue microarray constructs of patients treated with radical or partial nephrectomy for ccRCC between 1997-2010. Comprehensive clinical and pathologic data elements were collected. A prognostic marker score (MS) was defined as favorable if ≤4 biomarkers were altered; unfavorable if >4 biomarkers were altered. The relationship between MS and aggressive pathological features and oncological outcomes was evaluated. Results: The study included 452 patients, 277 males (61%). Median age was of 57 years (range, 17-85) and median follow up of 20 months (range, 0-150). The tumors demonstrated extrarenal extension (pT3-T4) in 120 (27%) patients and advanced grade (G 3/4) in 169 (37%). Regional nodal involvement and systemic metastases at the time of nephrectomy was present in 22 (5%) and 51(11%) patients, respectively. Unfavorable MS was found in 80 (18%) patients and was associated with distant and nodal metastasis, advanced T stage, advanced grade, tumor necrosis, sarcomatoid differentiation, lymphovascular invasion, fat invasion, adrenal involvement, and presence of venous thrombus (p < .05). A statistically significant correlation between unfavorable MS and disease recurrence (HR 6.5 and p = 0.01) and a correlation approaching significance with cancer specific mortality (HR 3.4 and p = 0.06) was demonstrated in Kaplan Meier survival analysis. In a multivariate Cox regression analysis, unfavorable MS was an independent predictor of disease recurrence (HR 2.268, CI 1.00-5.12 p = 0.049). Conclusions: The cumulative number of aberrantly expressed cell cycle biomarkers correlates with aggressive pathological features and inferior oncologic outcomes. Our findings support prospective pathway-based exploration of biomarkers to augment current clinico-pathologic predictors of oncologic outcomes in ccRCC.