Aberrant DNA Methylation of NPTX2 as an Indicator of Malignant Behavior in Thymic Epithelial Tumors

Simple Summary Metastatic or inoperable thymic carcinoma (TC) has a very poor prognosis. Since this tumor is rare, few clinical trials have been conducted to date, and thus, the development of new drugs is slow. The aberrant pathways involved in TC need to be examined in more detail in order to identify novel target molecules for TC therapy. Next-generation sequencing has been used to comprehensively investigate genetic alterations in thymic epithelial tumors (TET). However, limited information is currently available on epigenetic alterations. In the present study, genome-wide screening was conducted on aberrantly methylated CpG islands in TET, and 92 genes were identified. We then focused on the DNA methylation and mRNA and protein expression of NPTX2 in TET. The DNA methylation level of NPTX2 was higher, while its mRNA and protein expression levels were lower in TC than in the normal thymus and thymoma. Furthermore, relapse-free survival was shorter in patients with high NPTX2 DNA methylation levels than in those with low DNA methylation levels. Collectively, the present results indicate the potential use of NPTX2 as a tumor suppressor in TC.Abstract Thymic epithelial tumors (TET) consist of thymomas, thymic carcinoma (TC), and neuroendocrine tumors of the thymus (NECTT). Genetic and epigenetic alterations in TET have been the focus of recent research. In the present study, genome-wide screening was performed on aberrantly methylated CpG islands in TET, and this identified neuronal pentraxin 2 (NTPX2) as a significantly hypermethylated CpG island in TC relative to thymomas. NPTX2 is released from pre-synaptic cells in response to neuronal activity/seizure, and plays a role in host immunity and acute inflammation. TET samples were obtained from 38 thymomas, 25 TC, and 6 NECTT. The DNA methylation, mRNA, and protein expression levels of NPTX2 were examined. The DNA methylation rate of the NPTX2 gene was significantly higher in TC than in the normal thymus and thymomas, except B3. The mRNA expression level of NPTX2 was lower in TC than in the normal thymus. An inverse relationship was observed between mRNA expression levels and methylation levels. Relapse-free survival was shorter in patients with high NPTX2 DNA methylation levels than in those with low DNA methylation levels. NECTT showed very high mRNA and protein expression levels and low DNA methylation levels of NPTX2. NPTX2 may function as a tumor suppressor in TC, and have an oncogenic function in NECTT.