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Open AccessArticle

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

1
Department of Pathology, Seoul National University Hospital, Seoul 03080, Korea
2
Department of Pathology, Seoul National University College of Medicine, Seoul 03080, Korea
3
Division of Clinical Bioinformatics, Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Korea
4
Seoul National University College of Medicine, Seoul 03080, Korea
5
Cancer Research Institute, Seoul National University, Seoul 03080, Korea
6
Department of Pathology, Seoul National University Bundang Hospital, Seongnam-si 46371, Korea
7
Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this study.
Cancers 2020, 12(6), 1669; https://doi.org/10.3390/cancers12061669
Received: 19 May 2020 / Revised: 11 June 2020 / Accepted: 18 June 2020 / Published: 23 June 2020
(This article belongs to the Section Cancer Pathophysiology)
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. View Full-Text
Keywords: malignant lymphoma; marginal zone lymphoma; genetics; whole exome sequencing; RNA sequencing malignant lymphoma; marginal zone lymphoma; genetics; whole exome sequencing; RNA sequencing
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Koh, J.; Jang, I.; Choi, S.; Kim, S.; Jang, I.; Ahn, H.K.; Lee, C.; Paik, J.H.; Kim, C.W.; Lim, M.S.; Kim, K.; Jeon, Y.K. Discovery of Novel Recurrent Mutations and Clinically Meaningful Subgroups in Nodal Marginal Zone Lymphoma. Cancers 2020, 12, 1669.

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