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

• Main Authors: Jiwon Koh, Insoon Jang, Seongmin Choi, Sehui Kim, Ingeon Jang, Hyun Kyung Ahn, Cheol Lee, Jin Ho Paik, Chul Woo Kim, Megan S. Lim, Kwangsoo Kim, Yoon Kyung Jeon
• Format: Article
• Language: English
• Published: MDPI AG 2020-06-01
• Series: Cancers
• Subjects: malignant lymphoma; marginal zone lymphoma; genetics; whole exome sequencing; RNA sequencing
• Online Access: https://www.mdpi.com/2072-6694/12/6/1669

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 (<i>n</i> = 8) and validated their features in an extended cohort (<i>n</i> = 30). Novel mutations in <i>NFKBIE</i> and <i>ITPR2</i> 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 (<i>p</i> = 0.014), a greater proportion of large cells (<i>p</i> = 0.009), and higher MYC expression (<i>p</i> = 0.026). We suggest that NMZL has unique features and, in this study, we provide information as to the heterogeneity of this enigmatic entity.