Optimized p53 immunohistochemistry is an accurate predictor of TP53 mutation in ovarian carcinoma.
Optimized p53 immunohistochemistry is an accurate predictor of TP53 mutation in ovarian carcinoma.
复制标题
DOI：
10.1002/cjp2.53
复制
发表时间：
2016-10
影响因子：
4.1
通讯作者：
Brenton, James D
中科院分区：
文献类型：
--
作者：
Kobel, Martin;Piskorz, Anna M;Lee, Sandra;Lui, Shuhong;LePage, Cecile;Marass, Francesco;Rosenfeld, Nitzan;Mes Masson, Anne-Marie;Brenton, James D
TP 53突变在高级别浆液性卵巢癌（HGSOC）中普遍存在，TP 53突变的存在可区分高级别和低级别浆液性癌，现在是针对突变型p53的临床试验的重要生物标志物。p53免疫组织化学（IHC）被广泛用作TP 53突变的替代物，但其准确性尚未建立。本研究的目的是测试改进的p53 IHC方法是否可以可靠地预测下一代测序（NGS）独立鉴定的TP 53突变。对171例HGSOC和80例类甲状腺癌（EC）进行了4次临床p53 IHC测定和TP 53的标记扩增子NGS。将p53表达评分为过表达（OE）、完全缺失（CA）、胞浆型（CY）或野生型（WT）。p53 IHC作为二元分类器进行评价，其中任何异常染色预测有害的TP 53突变，作为三元分类器进行评价，其中OE、CA或WT染色分别预测功能获得（GOF或非同义）、功能丧失（LOF，包括停止增益、插入缺失、剪接）或不可检测的TP 53突变（NDM）。在169/171（99%）HGSOC和7/80（8.8%）EC中检测到有害的TP 53突变。对于二元和三元预测，性能最佳的IHC检测的总体准确度分别为0.94和0.91，在对不一致病例进行二次分析后，其提高至0.97（灵敏度0.96，特异性1.00）和0.95。预测LOF突变的灵敏度较低，为0.76，因为p53 IHC在13例LOF突变的HGSOC中检测到突变的p53蛋白。4例（2.3%）HGSOC中可见与LOF相关的CY染色。优化的p53 IHC对TP 53突变的特异性接近100%，其高阴性预测值在临床上有用，因为它可以排除低级别浆液性肿瘤的可能性。4.1%的HGSOC病例具有可检测的WT染色，同时携带TP 53 LOF突变，这将突变的二元预测的灵敏度限制为96%。
TP53 mutations are ubiquitous in high‐grade serous ovarian carcinomas (HGSOC), and the presence of TP53 mutation discriminates between high and low‐grade serous carcinomas and is now an important biomarker for clinical trials targeting mutant p53. p53 immunohistochemistry (IHC) is widely used as a surrogate for TP53 mutation but its accuracy has not been established. The objective of this study was to test whether improved methods for p53 IHC could reliably predict TP53 mutations independently identified by next generation sequencing (NGS). Four clinical p53 IHC assays and tagged‐amplicon NGS for TP53 were performed on 171 HGSOC and 80 endometrioid carcinomas (EC). p53 expression was scored as overexpression (OE), complete absence (CA), cytoplasmic (CY) or wild type (WT). p53 IHC was evaluated as a binary classifier where any abnormal staining predicted deleterious TP53 mutation and as a ternary classifier where OE, CA or WT staining predicted gain‐of‐function (GOF or nonsynonymous), loss‐of‐function (LOF including stopgain, indel, splicing) or no detectable TP53 mutations (NDM), respectively. Deleterious TP53 mutations were detected in 169/171 (99%) HGSOC and 7/80 (8.8%) EC. The overall accuracy for the best performing IHC assay for binary and ternary prediction was 0.94 and 0.91 respectively, which improved to 0.97 (sensitivity 0.96, specificity 1.00) and 0.95 after secondary analysis of discordant cases. The sensitivity for predicting LOF mutations was lower at 0.76 because p53 IHC detected mutant p53 protein in 13 HGSOC with LOF mutations. CY staining associated with LOF was seen in 4 (2.3%) of HGSOC. Optimized p53 IHC can approach 100% specificity for the presence of TP53 mutation and its high negative predictive value is clinically useful as it can exclude the possibility of a low‐grade serous tumour. 4.1% of HGSOC cases have detectable WT staining while harboring a TP53 LOF mutation, which limits sensitivity for binary prediction of mutation to 96%.