PDF(Pubmed)
Abstract：
Neurofibromatosis type 2 (NF2) loss occurs in approximately 30% to 50% of diffuse pleural mesothelioma (DPM) with accumulation of yes-associated protein (YAP) 1 and transcriptional coactivator with PDZ-binding motif (TAZ) in tumor nuclei. NF2 and YAP/TAZ represent potential therapeutic targets. We investigated the performance of NF2-YAP/TAZ dual immunohistochemistry (IHC) in identifying DPM that harbors NF2 alterations and in distinguishing DPM from benign mesothelial proliferations. NF2-YAP/TAZ IHC was subsequently performed in a Discovery cohort of DPMs with (n = 10) or without (n = 10) NF2 alterations detected by next-generation sequencing (NGS) and 9 benign cases. The cutoff values for loss of NF2 expression and YAP/TAZ overexpression using IHC were determined in the Discovery cohort. The performance characteristics of NF2-YAP/TAZ IHC were investigated in a Validation cohort (20 DPMs and 10 benign cases). In the Discovery cohort, all DPMs with NF2 alterations using NGS showed NF2 IHC scores of <2, whereas all NF2-wild-type DPMs showed scores of ≥2. NF2-altered DPMs had significantly higher YAP/TAZ H-scores (P < .001) than NF2-wild-type DPM and benign pleura (median H-scores: 237.5 [range, 185-275], 130.0 [range, 40-225], and 10.0 [range, 0-75], respectively). NF2-YAP/TAZ IHC demonstrated 95.2% sensitivity, 100% specificity, 100% positive predictive value, and 95% negative predictive value for detecting NF2 alterations in DPM (n = 40) with NGS as the gold standard and 87.5% sensitivity and 100% specificity for distinguishing DPM (n = 40) from benign mesothelial proliferations (n = 19). NF2-YAP/TAZ IHC has a high sensitivity and specificity for detecting NF2 alterations in DPM and a high specificity for malignancy, highlighting potential utility for guiding NF2-targeted therapies and distinguishing DPM from benign mimics.
摘要：
2型神经纤维瘤病（NF2）丢失发生在大约30％至50％的弥漫性胸膜间皮瘤（DPM）中，并在肿瘤核中积累了与PDZ结合基序（TAZ）相关的蛋白（YAP）1和转录共激活因子。NF2和YAP/TAZ代表潜在的治疗靶标。我们研究了NF2-YAP/TAZ双重免疫组织化学（IHC）在识别具有NF2改变的DPM以及将DPM与良性间皮增殖区分开方面的性能。随后在具有(n=10)或不具有(n=10)通过下一代测序(NGS)检测到的NF2改变和9例良性病例的DPM的发现队列中进行NF2-YAP/TAZIHC。在Discovery群组中确定NF2表达丧失和使用IHC的YAP/TAZ过表达的截断值。在验证队列（20例DPM和10例良性病例）中研究了NF2-YAP/TAZIHC的性能特征。在“发现”队列中，使用NGS进行NF2改变的所有DPM均显示NF2IHC评分<2,而所有NF2野生型DPM均显示评分≥2.NF2改变的DPM的YAP/TAZH评分（P<.001）显着高于NF2野生型DPM和良性胸膜（中位数H评分：237.5[范围，185-275],130.0[范围,40-225],和10.0[范围，0-75],分别)。NF2-YAP/TAZIHC显示95.2％的敏感性，100%特异性,100%阳性预测值，以NGS为金标准，检测DPM中NF2改变（n=40）的阴性预测值为95％，将DPM（n=40）与良性间皮增殖（n=19）区分为87.5％的敏感性和100％的特异性。NF2-YAP/TAZIHC对检测DPM中的NF2改变具有高灵敏度和特异性，对恶性肿瘤具有高特异性，强调指导NF2靶向治疗和区分DPM与良性模拟的潜在效用。
