Abstract 2513: Mutational and transcriptional landscape of nodal marginal zone lymphoma
Authors: Koh Jiwon , Choi Seongmin , Jang Insoon , Kim Sehui , Lee Cheol , Paik Jin Ho , Kim Kwangsoo , Jeon Yoon Kyung 
Published: August 2019

Abstract
Nodal marginal zone lymphoma (NMZL) is a rare B-cell neoplasm lacking disease-defining markers. In this study, we aimed to determine the mutational profile of Asian NMZLs and report novel genetic features of this disease. We performed WES on FFPE samples of eight Korean NMZLs and two matched non-neoplastic tissue samples. For unmatched cases, additional variant filtering was performed to minimize germline contamination. RNAseq was performed on six NMZL FFPE samples with acceptable samples quality. A total of 394 non-synonymous variants in 370 genes were found with the mean number of variants per case of 49.3 (range 14 – 98). We selected 93 candidate NMZL genes (CNGs) based on the following criteria: (i) genes with mutations in ≥ 2 patients; (ii) genes with mutations in either of two cases with matched control; (iii) genes with mutations in at least one case and reported to have biological roles in B-cell lymphomas. Mutations in genes involved in chromatin remodeling including KMT2D (25%), HIST1H1E (25%), and HIST1H1B (13%) were observed, which was consistent with previous studies. Genes encoding key components of B-cell receptor (BCR) signaling and related pathways were also affected, including CD79B (25%), CARD11 (13%) and BCL6 (13%). Of note, NFKBIE (c.759_762delTTAC) frameshift mutation was found in one patient; this mutation was proven to be loss-of-function in nature, resulting in deregulation of NF-κB signaling. Identical mutation was reported in Hodgkin lymphoma and primary mediastinal B-cell lymphoma, however, this is the first report of this mutation in NMZL. Genes involved in immune response including MYD88 (13%), PIM1 (13%), CD70 (13%) and TNFRSF14 (13%) were also mutated, suggesting the linkage between immune dysregulation and NMZL pathogenesis. At the transcriptome level, three samples were consistently clustered together. This group of patients was characterized by higher Ki-67 proliferation index compared to the others, and was associated with older age, higher serum LDH level and higher IPI score. Gene set analysis (GSA) based on lymphoma-specific gene sets from SignatureDB (https://lymphochip.nih.gov/signaturedb/) showed significant association between XBP1 target
genes and these high Ki-67 group (P = 0.024). In summary, this study showed high prevalence of mutations in chromatin remodeling and BCR signaling pathway, readdressing the importance of these pathways in NMZL. Several novel genetic alterations in NMZL were found including NFKBIE c.759_762delTTAC, warranting further validation to clarify the significance of these alterations. We also found that NMZLs with high Ki-67 index were associated with specific gene expression profile, providing clue to the explanation for the heterogeneity of NMZLs.
Citation Format: Jiwon Koh, Seongmin Choi, Insoon Jang, Sehui Kim, Cheol Lee, Jin Ho Paik, Kwangsoo Kim, Yoon Kyung Jeon. Mutational and transcriptional landscape of nodal marginal zone lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2513.