Center for Human Genetics, School of Medicine, Université Catholique de Louvain, Cliniques universitaires Saint-Luc, B-1200 Brussels, Belgium.
Hum Pathol. 2011 Dec;42(12):1897-910. doi: 10.1016/j.humpath.2010.06.021. Epub 2011 Jun 12.
Although evidence suggests an inverse relationship between microsatellite instability and p53 alterations in colorectal cancer, no study has thoroughly examined the use of p53 immunohistochemistry in phenotyping colorectal cancers. We investigated the value of p53 immunohistochemistry in microsatellite instability-positive colorectal cancers prescreening and attempted to clarify the relationship between DNA mismatch repair system and p53 pathway. In a series of 104 consecutive colorectal cancers, we performed p53 immunohistochemistry, TP53 mutational analysis, DNA mismatch repair system efficiency evaluation (DNA mismatch repair system immunohistochemistry, microsatellite instability status, MLH1/MSH2 germ line, and BRAF, murine double minute 2, and p21 immunohistochemistry. Microsatellite instability high was observed in 25 of 104 colorectal cancers, with DNA mismatch repair system protein loss (24/25) and germ line (8/25) or BRAF mutations (8/25). p53 immunohistochemistry revealed 3 distinct patterns of expression: complete negative immunostaining associated with truncating TP53 mutations (P < .0001), diffuse overexpression associated with missense TP53 mutations (P < .0001), and restricted overexpression characterized by a limited number of homogenously scattered strongly positive tumor cells in 36.5% of colorectal cancers. This latest pattern was associated with wild-type TP53 and microsatellite instability high colorectal cancers (P < .0001) including all Lynch tumors (8/8), but its presence among 22% of DNA mismatch repair system-competent colorectal cancers decreased its positive predictive value (55.2% [95% confidence interval, 45%-65%]). It was also correlated with murine double minute 2 overexpression (P < .0001) and inversely with p21 loss (P = .0002), independently of microsatellite instability status. In conclusion, a restricted pattern of p53 overexpression is preferentially associated with microsatellite instability high phenotype and could, therefore, be of clinical use as signal for microsatellite instability analysis in a large-scale tumor screening. Its association with concomitant murine double minute 2 overexpression suggests an alternative mechanism of p53 pathway deregulation.
虽然有证据表明微卫星不稳定性与结直肠癌中的 p53 改变呈负相关，但尚无研究彻底检查 p53 免疫组织化学在结直肠癌表型中的作用。我们研究了 p53 免疫组织化学在微卫星不稳定阳性结直肠癌预筛选中的价值，并试图阐明 DNA 错配修复系统与 p53 通路之间的关系。在一系列 104 例连续结直肠癌中，我们进行了 p53 免疫组织化学、TP53 突变分析、DNA 错配修复系统效率评估（DNA 错配修复系统免疫组织化学、微卫星不稳定状态、MLH1/MSH2 种系和 BRAF、鼠双微体 2、p21 免疫组织化学）。在 104 例结直肠癌中，有 25 例出现微卫星不稳定高，DNA 错配修复系统蛋白丢失（24/25）和种系（8/25）或 BRAF 突变（8/25）。p53 免疫组织化学显示 3 种不同的表达模式：与截断 TP53 突变相关的完全阴性免疫染色（P<0.0001）、与错义 TP53 突变相关的弥漫过表达（P<0.0001）和以有限数量均匀散布的强阳性肿瘤细胞为特征的受限过表达，在 36.5%的结直肠癌中。这种最新的模式与野生型 TP53 和微卫星不稳定高结直肠癌（P<0.0001）相关，包括所有 Lynch 肿瘤（8/8），但在 22%的 DNA 错配修复系统有效的结直肠癌中存在，降低了其阳性预测值（55.2%[95%置信区间，45%-65%]）。它还与鼠双微体 2 过表达相关（P<0.0001），与 p21 缺失呈负相关（P=0.0002），独立于微卫星不稳定状态。总之，受限的 p53 过表达模式优先与微卫星不稳定高表型相关，因此可以作为大规模肿瘤筛查中微卫星不稳定分析的信号，具有临床应用价值。它与同时的鼠双微体 2 过表达相关，提示 p53 通路失调控的另一种机制。
