Lacombe L, Orlow I, Silver D, Gerald W L, Fair W R, Reuter V E, Cordon-Cardo C
Urology Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Oncol Res. 1996;8(10-11):409-14.
The p21WAF1/CIP1 gene is regulated by p53 and encodes a cyclin-dependent kinase (Cdk)-inhibitor involved in senescence and cell quiescence. The role of p21 as a negative regulator of cell proliferation suggests that it may function as a tumor suppressor gene. However, only a few mutations of the p21WAF1/CIP1 gene have been reported to date. In order to assess potential p21WAF1/CIP1 gene alterations in human bladder cancer, we have examined this gene and its encoded product in a well-characterized cohort of 27 primary bladder tumors. Mobility shifts by single-strand conformation polymorphism in the p21WAF1/CIP1 gene were identified in 2 cases. Sequencing analyses revealed that one of these cases had point mutations in the 3' untranslated region, while the other case had a frame shift mutation at positions 322 (C to A) and a deletion of 8 nucleotides (323-->331; CCG-->ACG, codon 81 Arg-->Thr) that produced a stop signal at codon 83 (Gly--Stop). This tumor had a p21-negative phenotype by immunohistochemistry, but did not lose any allele. We further characterized these cases by the study of TP53 mutations using single-strand conformation polymorphism (PCR-SSCP) and sequencing, as well as immunohistochemical assays. Seven mobility shifts were identified and seven cases showed p53 nuclear accumulation. The two cases displaying mutated p21WAF1/CIP1 had wild-type TP53. It is concluded that p21WAF1/CIP1 gene aberrations are infrequent in bladder carcinoma but may be occasionally identified in primary bladder tumors.
p21WAF1/CIP1基因受p53调控，编码一种参与衰老和细胞静止的细胞周期蛋白依赖性激酶（Cdk）抑制剂。p21作为细胞增殖的负调节因子，提示其可能作为肿瘤抑制基因发挥作用。然而，迄今为止，仅报道了少数p21WAF1/CIP1基因的突变。为了评估人膀胱癌中潜在的p21WAF1/CIP1基因改变，我们在一组特征明确的27例原发性膀胱肿瘤中检测了该基因及其编码产物。在2例病例中发现了p21WAF1/CIP1基因单链构象多态性导致的迁移率改变。测序分析显示，其中1例在3'非翻译区存在点突变，而另1例在322位（C突变为A）发生移码突变，并缺失8个核苷酸（323→331；CCG→ACG，密码子81精氨酸→苏氨酸），在密码子83（甘氨酸→终止密码子）处产生终止信号。该肿瘤经免疫组织化学检测呈p21阴性表型，但未丢失任何等位基因。我们通过单链构象多态性（PCR-SSCP）和测序以及免疫组织化学检测对TP53突变进行研究，进一步对这些病例进行了特征分析。共识别出7个迁移率改变，7例显示p53核内积聚。表现出p21WAF1/CIP1突变的2例病例具有野生型TP53。结论是，p21WAF1/CIP1基因畸变在膀胱癌中不常见，但偶尔可在原发性膀胱肿瘤中发现。
