Abstract
Nodal marginal zone lymphoma (NMZL) is a rare B-cell neoplasm, the genetic and transcriptomic landscape of which are unclear. Using high-throughput sequencing for whole-exome and transcriptome, we investigated the genetic characteristics of NMZL in a discovery cohort (n = 8) and validated their features in an extended cohort (n = 30). Novel mutations in NFKBIE and ITPR2 were found in 7.9% (3/38) and 13.9% (5/36), respectively, suggesting roles for the NF-κB pathway and B-cell-receptor-mediated calcium signaling pathway in the pathogenesis of NMZL. RNA-seq showed that NMZLs were characterized by an aberrant marginal zone differentiation, associated with an altered IRF4-NOTCH2 axis and the enrichment of various oncogenic pathways. Based on gene expression profile, two subgroups were identified. Compared with subgroup 1, subgroup 2 showed the following: the significant enrichment of cell cycle-associated and MYC-signaling pathways, a more diverse repertoire of upstream regulators, and higher Ki-67 proliferation indices. We designated two subgroups according to Ki-67 labeling, and subgroup 2 was significantly associated with a shorter progression-free survival (p = 0.014), a greater proportion of large cells (p = 0.009), and higher MYC expression (p = 0.026). We suggest that NMZL has unique features and, in this study, we provide information as to the heterogeneity of this enigmatic entity.
Highlights
IntroductionNodal marginal zone lymphoma (NMZL) is a rare mature B-cell neoplasm that accounts for about
Nodal marginal zone lymphoma (NMZL) is a rare mature B-cell neoplasm that accounts for about1–2% of all B-cell non-Hodgkin lymphoma (NHL) [1,2]
Considering the small number of sample replicates used in this study, the gene set permutation gene set enrichment analysis (GSEA) algorithm [12] was used to identify the pathways enriched in NMZLs compared with non-neoplastic lymph nodes (LNs)
Summary
Nodal marginal zone lymphoma (NMZL) is a rare mature B-cell neoplasm that accounts for about. Found frequent genetic alterations that affect chromatin modifiers and the NOTCH pathway and suggested that PTPRD mutation is the key genetic feature of NMZLs [6]. In another study performed on Swiss patients with NMZL, Pillonel et al reported recurrent BRAF mutations, suggesting that. Despite the partially overlapping genetic features of NMZLs reported by the two studies (altered chromatin remodeling and the NOTCH pathway), the key findings of each study—PTPRD and BRAF mutations—were not reproducible. This suggests the pathogenic heterogeneity of NMZL, emphasizing the need for investigation of its genetic alterations. We identified novel genetic alterations, dysregulated pathways, and distinct subgroups of NMZLs
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