AbstractBackgroundMesothelioma is a neoplastic disease associated with asbestos exposure. It is highly malignant and has a poor prognosis; thus, early detection is desirable. Recent whole‐genome analysis has revealed that mesothelioma is characterized by a high frequency of mutations in a set of genes involved in the Hippo pathway, such asNF2andLATS2. However, a rapid, simple, and precise method for finding mesothelioma with these mutations has not yet been established.MethodsClustering of Hippo pathway gene alteration groups and the differential expression of each gene in mesothelioma patients were analyzed using The Cancer Genome Atlas database. Gene expression levels in various tumors and normal tissues were analyzed using public databases. Knockdown or transient expression ofYAP1orTAZwas performed to evaluate the regulation of gene expression by these genes. NT‐proBNP was measured in the pleural effusions of 18 patients and was compared with NF2 expression in five cases where cell lines had been successfully established.ResultsNPPBmRNA expression was markedly higher in the group of mesothelioma patients with Hippo pathway gene mutations than in the group without them.NPPBexpression was low in all normal tissues except heart, and was highest in mesothelioma. Mesothelioma patients in the highNPPBexpression group had a significantly worse prognosis than those in the lowNPPBexpression group.NPPBexpression was suppressed by knockdown ofYAP1orTAZ. NT‐proBNP was abundant in the effusions of mesothelioma patients and was particularly high in those with impaired NF2 expression.ConclusionsNPPB, whose levels can be measured in pleural effusions of mesothelioma patients, has the potential to act as a biomarker to detectNF2‐Hippo pathway gene alterations and/or predict patient prognosis. Additionally, it may provide useful molecular insights for a better understanding of mesothelioma pathogenesis and for the development of novel therapies.