Discovery of Novel Recurrent Mutations and Clinically Meaningful Subgroups in Nodal Marginal Zone Lymphoma

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.

Mutational landscape of marginal zone B-cell lymphomas of various origin: organotypic alterations and diagnostic potential for assignment of organ origin

“…Fig. 5) [20,21,41]. A total of 34 samples sequenced by WES, accounting for 1593 variants, were included in the final list.…”

From marginal zone lymphoma to aggressive diffuse large B-cell lymphoma: a whole-exome and clinicopathological characteristics analysis of transformed lymphoma

“…The present study revealed extensive genetic heterogeneity, there is a large number of genetic variations affecting many genes and pathways, re ecting the complexity of the HT process. Our results suggest that the genomic mutational landscape and CNA pro les of tMZL is much more complex than that of MZL [21,33,34]. We identi ed chromatin regulator genes were mutated in MZL (EP300) and tMZL (CREBBP and EP300), previous studies demonstrated that chromatin regulator genes mutations were early events in MZL [33,35].…”

“…Our results suggest that the genomic mutational landscape and CNA pro les of tMZL is much more complex than that of MZL [21,33,34]. We identi ed chromatin regulator genes were mutated in MZL (EP300) and tMZL (CREBBP and EP300), previous studies demonstrated that chromatin regulator genes mutations were early events in MZL [33,35]. Somatic mutations within regions of CNAs detected in our study, such as those in TNFAIP3, BCL10, and CD79B are associated with NF-κB activation and frequently mutated in de novo ABC-DLBCL [23,36].…”

From marginal zone lymphoma to aggressive diffuse large B-cell lymphoma: a whole-exome and clinicopathological characteristics analysis of transformed lymphoma

“…The present study revealed extensive genetic heterogeneity, there is a large number of genetic variations affecting many genes and pathways, re ecting the complexity of the HT process. Our results suggest that the genomic mutational landscape and CNA pro les of tMZL is much more complex than that of MZL [21,33,34]. We identi ed chromatin regulator genes were mutated in MZL (EP300) and tMZL (CREBBP and EP300), previous studies demonstrated that chromatin regulator genes mutations were early events in MZL [33,35].…”

“…Our results suggest that the genomic mutational landscape and CNA pro les of tMZL is much more complex than that of MZL [21,33,34]. We identi ed chromatin regulator genes were mutated in MZL (EP300) and tMZL (CREBBP and EP300), previous studies demonstrated that chromatin regulator genes mutations were early events in MZL [33,35]. Somatic mutations within regions of CNAs detected in our study, such as those in TNFAIP3, BCL10, and CD79B are associated with NF-κB activation and frequently mutated in de novo ABC-DLBCL [23,36].…”