Reles A, Wen W H, Schmider A, Gee C, Runnebaum I B, Kilian U, Jones L A, El-Naggar A, Minguillon C, Schönborn I, Reich O, Kreienberg R, Lichtenegger W, Press M F
Department of Pathology, University of Southern California School of Medicine, Los Angeles, CA 90033, USA.
Clin Cancer Res. 2001 Oct;7(10):2984-97.
The p53 tumor suppressor gene plays a central role in cell cycle regulation and induction of apoptosis. We analyzed p53 alterations and their impact on response to chemotherapy and clinical outcome in ovarian cancer patients.
One hundred seventy-eight ovarian carcinomas, snap frozen and stored at -80 degrees C, were analyzed for mutations of the p53 gene (exons 2-11) by single-strand conformation polymorphism and DNA sequencing and for p53 overexpression by immunohistochemistry (monoclonal antibody DO7).
p53 mutations were found in 56% (99 of 178) of the tumors, and 62% of these were located in evolutionary highly conserved domains of the gene. Time to progression and overall survival were significantly shortened in patients with p53 mutations compared with wild-type p53 (P = 0.029 and P = 0.014) and patients with mutations in highly conserved domains as opposed to nonconserved domains or wild-type p53 (P = 0.010 and P = 0.007). p53 protein overexpression (>10% positively stained nuclei) was found in 62% (110 of 178). Time to progression and overall survival were shorter in cases with p53 overexpression (cutpoint, 10%: P = 0.071 and P = 0.056) but only marginally significant. Resistance to adjuvant cisplatin or carboplatin chemotherapy was significantly more frequent in patients with p53 overexpression (P = 0.001) or p53 missense mutations (P = 0.008) than patients with normal p53.
p53 alterations correlate significantly with resistance to platinum-based chemotherapy, early relapse, and shortened overall survival in ovarian cancer patients in univariate analysis. In multivariable analysis though, p53 was not an independent prognostic factor.
p53肿瘤抑制基因在细胞周期调控和凋亡诱导中起核心作用。我们分析了卵巢癌患者中p53改变及其对化疗反应和临床结局的影响。
对178例速冻并保存在-80℃的卵巢癌进行分析，采用单链构象多态性和DNA测序检测p53基因（外显子2-11）的突变，采用免疫组织化学（单克隆抗体DO7）检测p53过表达。
56%（178例中的99例）的肿瘤发现有p53突变，其中62%位于该基因进化上高度保守的结构域。与野生型p53患者相比，p53突变患者的疾病进展时间和总生存期显著缩短（P = 0.029和P = 0.014），与非保守结构域或野生型p53突变患者相比，高度保守结构域突变患者的疾病进展时间和总生存期也显著缩短（P = 0.010和P = 0.007）。62%（178例中的110例）发现p53蛋白过表达（>10%细胞核阳性染色）。p53过表达患者（切点为10%：P = 0.071和P = 0.056）的疾病进展时间和总生存期较短，但仅具有边缘显著性。p�过表达（P = 0.001）或p53错义突变（P = 0.008）的患者对顺铂或卡铂辅助化疗的耐药性显著高于p53正常的患者。
在单因素分析中，p53改变与卵巢癌患者对铂类化疗的耐药性、早期复发和总生存期缩短显著相关。然而，在多变量分析中，p53不是一个独立的预后因素。
