Shahin M S, Hughes J H, Sood A K, Buller R E
Department of Obstetrics and Gynecology, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA.
Cancer. 2000 Nov 1;89(9):2006-17. doi: 10.1002/1097-0142(20001101)89:9<2006::aid-cncr18>3.3.co;2-z.
The prognostic significance and nature of p53 dysfunction in ovarian carcinoma is unclear. The relation between p53 overexpression, p53 mutations, and their effects on overall survival in primary ovarian carcinoma is explored.
Tumor specimens from 171 consecutive epithelial ovarian carcinomas were examined for overexpression of p53 protein with DO7 antibody. P53 mutations were determined by direct sequencing. The influences of conventional histopathologic prognostic factors and various p53 molecular alterations on overall survival were assessed.
Overall, 48.5% and 57.3% of the samples showed p53 overexpression and p53 mutation, respectively. Although neither p53 overexpression nor the mere presence of a p53 mutation impacted overall survival, the combination did prognosticate survival both in univariate and multivariate models. The authors' results suggest 4 mechanisms that may affect p53 dysfunction in nearly 100% of advanced stage ovarian carcinomas. These include null mutation, nonresponsive p53 (wild-type [wt] p53 sequence, DO7 negative), sequestration (wt p53 sequence, DO7 positive), and missense mutation. Median survival for these groups that constitute sequentially 21.3%, 20.5%, 12.3%, and 45.9% of the 122 Stage III or IV (International Federation of Gynecology and Obstetrics) cancers was 1.49, 1.31, 3.09, and 3.6 years, respectively. The nonresponsive p53 and null sequence tumors grouped together as functionally null convey the worst prognosis relative to missense mutations in a univariate model (P = 0.006). Functionally null p53 (P = 0.002), stage (P = 0.008), and optimal cytoreduction (P = 0.008) were independent prognostic factors by multivariate analysis.
Sequestration of wt p53 is unique to advanced stage ovarian carcinoma. Functionally null p53 represents an independent molecular predictor of compromised survival.
卵巢癌中p53功能障碍的预后意义和性质尚不清楚。本研究探讨p53过表达、p53突变及其对原发性卵巢癌总生存期的影响之间的关系。
采用DO7抗体检测171例连续的上皮性卵巢癌肿瘤标本中p53蛋白的过表达情况。通过直接测序确定p53突变。评估传统组织病理学预后因素和各种p53分子改变对总生存期的影响。
总体而言，分别有48.5%和57.3%的样本显示p53过表达和p53突变。虽然p53过表达和单纯存在p53突变均未影响总生存期，但在单变量和多变量模型中，两者结合确实可预测生存期。作者的研究结果提示了4种可能影响近100%晚期卵巢癌中p53功能障碍的机制。这些机制包括无义突变、无反应性p53（野生型[wt]p53序列，DO7阴性）、隔离（wt p53序列，DO7阳性）和错义突变。在122例国际妇产科联盟（FIGO）III期或IV期癌症中，这些组分别占21.3%、20.5%、12.3%和45.9%，其中位生存期分别为1.49年、1.31年、3.09年和3.6年。在单变量模型中，无反应性p53和无义序列肿瘤合并为功能无活性组，相对于错义突变，其预后最差（P = 0.006）。通过多变量分析，功能无活性p53（P = 0.002）、分期（P = 0.008）和最佳细胞减灭术（P = 0.008）是独立的预后因素。
wt p53的隔离是晚期卵巢癌所特有的。功能无活性p53是生存受损的独立分子预测指标。
