Halvorsen O J, Høstmark J, Haukaas S, Høisaeter P A, Akslen L A
Department of Pathology, The Gade Institute, Haukeland Hospital, University of Bergen, Bergen, Norway.
Cancer. 2000 Jan 15;88(2):416-24.
In prostate carcinoma, a very low frequency of point mutations of the tumor suppressor gene CDKN2/MTS1 (p16(INK4) ) has been reported, but deletions of 9p21 and inactivation by promoter methylation are observed more frequently. In the current study the authors evaluated the expression of p16 and CDK4 proteins and their prognostic significance in patients with clinically localized prostate carcinoma.
The levels of p16 and CDK4 proteins were quantitated by immunofluorescence flow cytometry, using paraffin embedded material, in 104 adenocarcinomas of the prostate after radical prostatectomy. These levels then were compared with 25 cases of benign prostate hyperplasia (BPH).
In prostatic carcinoma specimens, p16 protein was elevated significantly compared with BPH, with a median fluorescence index (FI) of 15.4 versus 10.7, respectively (P = 0.010). This was not the case for CDK4 protein, although p16 protein expression correlated significantly with CDK4 protein expression in BPH (Spearman rank correlation [R(S)] = 0.63) and carcinoma (R(S) = 0.78). In univariate survival analysis of the first 5 years, high levels of p16 protein expression (FI > 11.7) (P = 0.005), tumor greatest dimension, World Health Organization (WHO) histologic grade, capsular penetration, seminal vesicle invasion, positive surgical margins, lymph node involvement, and preoperative serum prostate specific antigen > 20 ng/mL all were significant predictors of biochemical failure. In multivariate survival analysis, high p16 protein expression (P = 0.015), age, WHO histologic grade, capsular penetration, and seminal vesicle involvement remained as independent predictors of biochemical failure.
These data suggest that increased expression of p16 protein, but not CDK4 protein, may be involved in the development of prostate carcinoma and may represent an independent predictor of biochemical failure after radical prostatectomy.
在前列腺癌中，肿瘤抑制基因CDKN2/MTS1（p16(INK4)）的点突变频率极低，但9p21缺失及启动子甲基化导致的失活却更为常见。在本研究中，作者评估了p16和CDK4蛋白的表达及其在临床局限性前列腺癌患者中的预后意义。
采用免疫荧光流式细胞术，利用石蜡包埋材料，对104例前列腺癌根治术后的前列腺腺癌组织中p16和CDK4蛋白水平进行定量分析。并将这些水平与25例良性前列腺增生（BPH）病例进行比较。
在前列腺癌标本中，与BPH相比，p16蛋白显著升高，中位荧光指数（FI）分别为15.4和10.7（P = 0.010）。CDK4蛋白情况并非如此，尽管p16蛋白表达在BPH（Spearman等级相关系数[R(S)] = 0.63）和癌组织（R(S) = 0.78）中均与CDK4蛋白表达显著相关。在最初5年的单因素生存分析中，p16蛋白高表达（FI > 11.7）（P = 0.005）、肿瘤最大直径、世界卫生组织（WHO）组织学分级、包膜侵犯、精囊侵犯、手术切缘阳性、淋巴结受累以及术前血清前列腺特异性抗原> 20 ng/mL均是生化复发的显著预测因素。在多因素生存分析中，p16蛋白高表达（P = 0.015）、年龄、WHO组织学分级、包膜侵犯和精囊受累仍是生化复发的独立预测因素。
这些数据表明，p16蛋白而非CDK4蛋白表达增加可能参与前列腺癌的发生发展，并且可能是前列腺癌根治术后生化复发的独立预测因素。
