Departments of Urology and Pathology (PK), University of Texas Southwestern Medical Center, Dallas, Texas.
J Urol. 2013 Nov;190(5):1662-7. doi: 10.1016/j.juro.2013.06.037. Epub 2013 Jun 20.
Cell cycle regulatory molecules are implicated in various stages of carcinogenesis. In this proof of principle study we systematically evaluate the association of aberrant expression of cell cycle regulators and proliferative markers and their effect on oncologic outcomes of patients with clear cell renal carcinoma.
Immunohistochemistry for Cyclin D, Cyclin E, p16, p21, p27, p53, p57 and Ki67 was performed on tissue microarray constructs of 452 patients treated with extirpative therapy for clear cell renal cell carcinoma between 1997 and 2010. Clinical and pathological data elements were collected. A prognostic marker score was defined as unfavorable if more than 4 biomarkers were altered. The relationship between marker score and pathological features and oncologic outcomes was evaluated.
Median age was 57 years (range 17 to 85) and median followup was 24 months (range 6 to 150). An unfavorable marker score was found in 55 (12.2%) patients and was associated with adverse pathological features. A significant correlation between unfavorable marker score and disease-free survival (HR 26.62, 95% CI 43.38-100.04, p=0.000) and with cancer specific survival (HR 8.15, 95% CI 74.42-101.56, p=0.004) was demonstrated on Kaplan-Meier survival analysis. On multivariate analysis an unfavorable marker score was an independent predictor of disease-free survival (HR 2.63, 95% CI 1.08-6.38, p=0.033).
The cumulative number of aberrantly expressed cell cycle and proliferative biomarkers correlates with aggressive pathological features and inferior oncologic outcomes in patients with clear cell renal cell carcinoma. Our findings indicate that interrogation of cell cycle and proliferative markers is feasible, and further prospective pathway based exploration of biomarkers is needed.
细胞周期调控分子参与了癌变的各个阶段。在这项原理验证研究中，我们系统地评估了细胞周期调节因子和增殖标志物的异常表达及其对接受根治性治疗的透明细胞肾细胞癌患者的肿瘤学结局的影响。
对 1997 年至 2010 年间接受根治性治疗的 452 例透明细胞肾细胞癌患者的组织微阵列构建体进行了细胞周期蛋白 D、E、p16、p21、p27、p53、p57 和 Ki67 的免疫组化染色。收集了临床和病理数据元素。如果有超过 4 个标志物发生改变，则将预后标志物评分定义为不利。评估了标志物评分与病理特征和肿瘤学结局之间的关系。
中位年龄为 57 岁（范围 17 至 85 岁），中位随访时间为 24 个月（范围 6 至 150 个月）。55 例（12.2%）患者的标志物评分不佳，与不良的病理特征相关。在 Kaplan-Meier 生存分析中，显著的相关性在无病生存率（HR 26.62，95%CI 43.38-100.04，p=0.000）和癌症特异性生存率（HR 8.15，95%CI 74.42-101.56，p=0.004）之间被证明。多变量分析表明，不利的标志物评分是无病生存率的独立预测因子（HR 2.63，95%CI 1.08-6.38，p=0.033）。
异常表达的细胞周期和增殖生物标志物的累积数量与透明细胞肾细胞癌患者侵袭性病理特征和较差的肿瘤学结局相关。我们的发现表明，对细胞周期和增殖标志物的检测是可行的，需要进一步进行基于通路的前瞻性标志物探索。
