Nuclear Receptor-Binding SU(VAR)3-9, Enhancer of Zeste, Trithorax Domain Structural Domain Protein 2 Serves as a Potential Prognostic Biomarker in Mantle Cell Lymphoma.

Nuclear receptor-binding SET structural domain protein 2 (NSD2) has been implicated in the pathogenesis of multiple cancers, exhibiting mutations or overexpression that contributes to tumor progression and poor clinical outcomes. In mantle cell lymphoma (MCL), approximately 15% of patients harbor NSD2 mutations; however, its clinical significance remains to be fully elucidated. In our study, we analyzed Next Generation Sequencing data from 147 MCL patients and identified NSD2 mutations in 8.84% (13/147) of cases, with 92.31% (12/13) demonstrating bone marrow involvement. Immunohistochemical evaluation of NSD2 protein expression in 39 patients revealed that high levels of NSD2 protein expression were associated with higher Mantle Cell Lymphoma International Prognostic Index scores, poorer treatment response, inferior overall survival, and progression-free survival. Furthermore, NSD2 expression is strongly associated with aggressive histologic variants, including elevated c-MYC protein expression and a high Ki-67 proliferation index. Our analysis of the cBioPortal database, encompassing lymphoma patients, uncovered that NSD2 mutations are most prevalent in MCL. Specifically, E1099K and T1150A point mutations were linked to poorer prognoses. Additionally, our examination of the Gene Expression Omnibus database (GSE93291) revealed a correlation between NSD2 messenger RNA (mRNA) expression levels and MKI67, with elevated NSD2 mRNA expression being associated with reduced survival rates. Tumor-infiltrating immune cell analysis with CIBERSORT in GSE93291 revealed the correlation with increased intratumoral regulatory T cells. According to our research, NSD2 mutations exhibit extremely aggressive biological behavior, and a worse prognosis is associated with higher levels of NSD2 in both mRNA and protein expression. We believe that NSD2 stands as a valuable prognostic marker and a potential therapeutic target in MCL.