Rose Stephen L, Goodheart Michael J, DeYoung Barry R, Smith Brian J, Buller Richard E
Holden Comprehensive Cancer Center, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, The University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242, USA.
Clin Cancer Res. 2003 Mar;9(3):1028-32.
p21 is a direct p53 response gene. Although several studies have correlated p21 and p53 expression, only one has evaluated p21 expression as a function of sequenced p53 gene mutation. We hypothesize that such an analysis may be useful in prognosticating outcome for individuals diagnosed with epithelial ovarian cancer.
DNA from the primary ovarian cancers of 267 patients was studied. p53 mutations were directly sequenced. Two percent or greater nuclear staining with WAF1/CIP1 monoclonal antibody was determined by a hazard ratio analysis to constitute positive p21 expression.
Positive p21 nuclear staining occurred more frequently in p53 wild-type ovarian tumors than tumors found to have a p53 mutation (P = 0.001). Positive p21 staining conferred an overall survival advantage (P = 0.02). p21 expression in cancers with p53 missense mutations was not prognostic but did show a strong trend toward significance in the wild-type p53 subset (P = 0.056). Surprisingly, positive p21 staining reflected compromised survival for individuals with p53-null ovarian cancers (P = 0.005). The mean expression level for p21-positive stains in the wild-type group was greater than in null p53 cancers (23 versus 11%; P = 0.001). A Cox multivariable analysis revealed p21 to be a strong independent prognostic factor in p53-null ovarian cancer (P = 0.02).
p21 expression is closely related to sequenced p53 mutations. This is the first study of positive p21 staining as an independent poor prognostic factor in p53-null ovarian cancer. A dual role for p21 activity, dependent on levels of expression, appears to explain these paradoxical results and is consistent with a complex model for regulation of p21.
p21是一种直接的p53反应基因。尽管有多项研究将p21和p53的表达相关联，但仅有一项研究评估了p21表达与测序的p53基因突变的关系。我们推测，这样的分析可能有助于预测上皮性卵巢癌患者的预后。
研究了267例原发性卵巢癌患者的DNA。直接对p53突变进行测序。通过风险比分析确定，用WAF1/CIP1单克隆抗体进行核染色，染色率达到2%或更高则构成p21阳性表达。
p21核染色阳性在p53野生型卵巢肿瘤中比发现有p53突变的肿瘤更常见（P = 0.001）。p21阳性染色赋予总体生存优势（P = 0.02）。p53错义突变癌症中的p21表达无预后意义，但在野生型p53亚组中确实显示出强烈的显著趋势（P = 0.056）。令人惊讶的是，p21阳性染色反映了p53缺失型卵巢癌患者的生存受损（P = 0.005）。野生型组中p21阳性染色的平均表达水平高于p53缺失型癌症（23%对11%；P = 0.001）。Cox多变量分析显示，p21是p53缺失型卵巢癌的一个强有力的独立预后因素（P = 0.02）。
p21表达与测序的p53突变密切相关。这是第一项将p21阳性染色作为p53缺失型卵巢癌独立不良预后因素的研究。p21活性的双重作用，取决于表达水平，似乎可以解释这些矛盾的结果，并且与p21调控的复杂模型一致。
