CYTOPLASMIC ACCUMULATION OF P53 PROTEIN - AN INDEPENDENT PROGNOSTIC INDICATOR IN COLORECTAL ADENOCARCINOMAS
CYTOPLASMIC ACCUMULATION OF P53 PROTEIN - AN INDEPENDENT PROGNOSTIC INDICATOR IN COLORECTAL ADENOCARCINOMAS
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DOI：
10.1093/jnci/86.9.681
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发表时间：
1994-05-04
影响因子：
10.3
通讯作者：
LEE, AKC
中科院分区：
文献类型：
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作者：
BOSARI, S;VIALE, G;LEE, AKC
背景：p53基因(又称TP53)的异常经常导致突变蛋白的合成，这些突变蛋白聚集在肿瘤细胞的细胞核和/或细胞质中。细胞内P53蛋白积聚可能是乳腺癌、肺癌、卵巢癌、胃癌和结直肠癌预后不良的指标。特定类别的P53基因突变，通过特征性的亚细胞P53蛋白积聚模式进行检测，可能是有用的预后指标。目的：探讨大肠癌患者肿瘤细胞胞核和胞浆内P53蛋白积聚的预后价值。方法：用抗体Pab1801和CM1免疫细胞化学方法检测206例随访5年以上的结直肠癌组织中P53蛋白的胞核和胞浆积聚情况。结果与以下临床病理参数相关：患者性别和年龄；肿瘤部位、分期和分级；以及肿瘤的DNA倍体状态。总体生存率和无瘤生存率采用Kaplan-Meier方法进行分析。分布差异采用Mantel-Cox方法进行分析。多因素分析采用COX比例风险模型。结果：PAb1801免疫组织化学染色显示46%(95/206)的病例有P53胞核积聚，而197例CM1免疫组织化学染色显示胞核和胞浆P53积聚分别为33%(65例)和50%(99例)。在单因素分析中，核P53蛋白(PAB 1801)和胞浆P53蛋白(CM1)积聚均与总生存率(P=0.0198和P=0.0017)和无瘤生存率(P=0.004和P=0.0016)显著相关。按肿瘤部位分析，核型P53(Pab)1801蛋白积聚仅在右半结肠有统计学意义(P=0.027)，而细胞质P53(CM1)蛋白积聚在左半结肠和直肠有统计学意义(P=0.0016)。在多因素分析中，只有细胞质P53(CM1)蛋白积聚与总体生存率差有关，E与无病生存率相关(P=0.006和P=0.002)。然而，随着DNA倍体状态的增加，细胞质P53(CM1)蛋白的积聚仅对无病生存有显著意义(P=0.035)。在左半结肠和直肠肿瘤患者中，胞浆P53(CM1)蛋白积聚是影响患者总生存期(P=0.007)和无瘤生存期(P=0.002)的最重要的预后指标。结论：胞浆P53(CM1)蛋白积聚是结直肠癌患者的独立预后指标，而核P53(Pab)(1801)蛋白积聚不是结直肠癌预后的独立指标。提示：细胞质P53(CM1)积聚可能是疾病复发高危患者的有用指标，这些患者可能受益于积极的辅助治疗。
Background: Aberrations of the p53 gene (also known as TP53) frequently lead to the synthesis of mutant proteins that accumulate in the nuclei and/or cytoplasm of neoplastic cells. Intracellular p53 protein accumulation may be an unfavorable prognostic parameter in breast, lung, ovarian, gastric, and colorectal cancers. Specific classes of p53 gene mutations, assayed by characteristic subcellular p53 protein accumulation patterns, may be useful prognostic indicators. Purpose: The prognostic value of nuclear and cytoplasmic p53 protein accumulation in the tumor cells of patients with colorectal carcinoma was studied. Methods: Antibodies PAb 1801 and CM1 were used for immunocytochemical assay of nuclear and cytoplasmic p53 protein accumulation in a retrospective series of colorectal carcinoma samples obtained from 206 patients who were followed for at least 5 years. Results were correlated with the following clinicopathologic parameters: patient sex and age; tumor site, stage, and grade; and DNA ploidy status of the tumors. Overall survival and disease-free survival were analyzed with the Kaplan-Meier method. Differences in distributions were analyzed using the Mantel-Cox method. Multivariate analysis was performed with the Cox proportional hazards model. Results: Immunostaining with PAb 1801 revealed nuclear p53 accumulation in 46% (95) of 206 cases, whereas CM1 immunostaining of 197 cases showed nuclear and cytoplasmic p53 accumulation in 33% (65 cases) and 50% (99 cases) of the cases, respectively. In univariate analysis, both nuclear p53(PAb 1801) and cytoplasmic p53(CM1) protein accumulations were significantly associated with poor overall survival (P = .0198 and P = .0017, respectively) and with disease-free survival (P = .004 and P = .0016, respectively). When patients were analyzed according to site of their tumors, nuclear p53(PAb) 1801 protein accumulation was statistically significant only in the right colon (P = .027), whereas cytoplasmic p53(CM1) protein accumulation was statistically significant in the left colon and rectum (P = .0016). In multivariate analysis, only cytoplasmic p53(CM1) protein accumulation was associated with poor overall survival and E with disease-free survival (P = .006 and P = .002, respectively). With the addition of DNA ploidy status, however, cytoplasmic p53(CM1) protein accumulation remained significant only for disease-free survival (P = .035). In patients with tumors of the left colon and rectum, cytoplasmic p53(CM1) protein accumulation was the most significant prognostic indicator for overall survival (P = .007) and disease-free survival (P = .002) after disease stage. Conclusion: Cytoplasmic p53(CM1) protein accumulation, but not nuclear p53(PAb) (1801) protein accumulation, is an independent prognostic parameter in patients with colorectal carcinomas. Implications: Cytoplasmic p53(CM1) accumulation may be a useful indicator of patients at high risk for disease recurrence who may benefit from aggressive adjuvant therapy.