10129-ET-2 Genetic profiling of meningiomas using cancer gene panel testing: exploration of molecular targeted therapies

Abstract Cancer gene panel testing has recently been covered by health insurance in Japan, and its clinical utility in brain tumors has been increasingly recognized. However, the majority of clinical reports have focused on gliomas, and data on meningiomas remain limited. At our institution, in addition to the approved panel, we have implemented an in-house panel (PleSSision-Rapid) capable of analyzing 156 genes in a wide range of brain tumors, including gliomas and meningiomas. This study aimed to identify genetic alterations characteristic of WHO grade 2/3 meningiomas and to explore potential molecular targets for therapy. We analyzed 62 cases of meningioma (grade 1: 44 cases; grade 2: 10 cases; grade 3: 8 cases) using the PleSSision-Rapid panel. Genetic alterations were compared between grade 1 and grade 2/3 tumors. Among the identified alterations, we focused on DDR2 as a potential therapeutic target and evaluated the effects of tyrosine kinase inhibitors using meningioma cell lines in vitro and in vivo. Compared with grade 1 meningiomas, grade 2/3 tumors showed a higher frequency of NF2 and KDM6A mutations, as well as copy number alterations in genes related to DNA repair, histone modification, and chromatin remodeling. DDR2 amplification was observed in a subset of grade 2/3 tumors. In cell lines with high DDR2 expression, tyrosine kinase inhibitors induced G1 cell cycle arrest and exhibited antitumor effects, whereas no such effects were observed in low-expressing cells. In vivo validation was performed using a xenograft model of a DDR2-high meningioma cell line, which also showed significant antitumor responses to the inhibitor. Our findings suggest that DDR2 may serve as a promising therapeutic target in high-grade meningiomas and provide a rationale for the development of novel molecular-targeted therapies.