Division of Cancer Epidemiology and Genetics, Science Applications International Corporation-Frederick, Inc., National Cancer Institute-Frederick, Frederick, MD, USA.
Cancer Epidemiol Biomarkers Prev. 2012 Sep;21(9):1555-64. doi: 10.1158/1055-9965.EPI-12-0261. Epub 2012 Jul 3.
Cell-cycle proteins are important predictive markers in urothelial carcinoma but may also exhibit exposure-specific heterogeneity.
Tumor tissue from 491 bladder cancer cases enrolled in the Maine and Vermont component of the New England Bladder Cancer Study was assembled as tissue microarrays and examined for aberrant expression of p53, p63, p16, cyclin D1, Rb, and Ki-67. The association between expression and histopathology, demographics, and cigarette smoking was examined using χ(2) tests, multivariable Poisson, and multinomial regression models.
We found that overexpression of p53 and Ki-67 was associated with high-stage/grade tumors [relative risk (RR), 1.26; P(trend) = 0.003; and RR, 3.21; P(trend) < 0.0001, respectively], whereas expression of p63 and p16 was decreased in high-stage/grade tumors (RR, 0.52; P(trend) < 0.0001; and RR, 0.88; P(trend) = 0.04, respectively). No significant aberrations of cell-cycle proteins were identified using various smoking variables and multiple statistical models.
The results of this population-based study of histologically confirmed urothelial carcinomas show significant aberration of cell-cycle proteins p53, p63, p16, and Ki-67, but not Rb or cyclin D1. p53 showed the most significant heterogeneity with respect to tumor stage and grade, especially when stratified for different staining intensities using novel digital image analysis techniques. Our findings do not support that smoking modifies expression of cell-cycle proteins.
Our study shows significant heterogeneity in the expression of key cell-cycle proteins that are associated with disease progression in bladder cancer. Further studies may lead to the identification of biomarkers and their multiplexed interactions as useful prognostic and therapeutic targets.
细胞周期蛋白是尿路上皮癌的重要预测标志物，但也可能表现出暴露特异性的异质性。
将来自新英格兰膀胱癌研究缅因州和佛蒙特州部分的 491 例膀胱癌病例的肿瘤组织组装成组织微阵列，并检查 p53、p63、p16、cyclin D1、Rb 和 Ki-67 的异常表达。使用 χ(2)检验、多变量泊松和多项回归模型检查表达与组织病理学、人口统计学和吸烟之间的关系。
我们发现，p53 和 Ki-67 的过度表达与高分期/分级肿瘤相关（相对风险 RR，1.26；P(趋势) = 0.003；RR，3.21；P(趋势) < 0.0001），而 p63 和 p16 的表达在高分期/分级肿瘤中降低（RR，0.52；P(趋势) < 0.0001；RR，0.88；P(趋势) = 0.04）。使用各种吸烟变量和多个统计模型均未发现细胞周期蛋白的显著异常。
这项基于人群的、经组织学证实的尿路上皮癌研究结果显示，细胞周期蛋白 p53、p63、p16 和 Ki-67 存在显著异常，但 Rb 或 cyclin D1 不存在异常。p53 与肿瘤分期和分级的相关性最为显著，尤其是使用新的数字图像分析技术对不同染色强度进行分层时。我们的研究结果不支持吸烟改变细胞周期蛋白的表达。
本研究显示，在膀胱癌中与疾病进展相关的关键细胞周期蛋白的表达存在显著异质性。进一步的研究可能会导致鉴定出生物标志物及其多重相互作用，作为有用的预后和治疗靶点。
