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Significant association between TNFAIP3 inactivation and biased immunoglobulin heavy chain variable region 4-34 usage in mucosa-associated lymphoid tissue lymphoma.

Accepted version
Peer-reviewed

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Type

Article

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Authors

Moody, Sarah 
Escudero-Ibarz, Leire 
Wang, Ming 
Clipson, Alexandra 
Ochoa Ruiz, Eguzkine 

Abstract

Both antigenic drive and genetic change play critical roles in the development of mucosa-associated lymphoid tissue (MALT) lymphoma, but neither alone is sufficient for malignant transformation, and lymphoma development critically depends on their cooperation. However, which of these different events concur and how they cooperate in MALT lymphomagenesis is totally unknown. To explore this, we investigated somatic mutations of 17 genes and immunoglobulin heavy chain variable region (IGHV) usage in 179 MALT lymphomas from various sites. We showed that: (1) there was a significant association between the biased usage of IGHV4-34 (binds to the carbohydrate I/i antigens) and inactivating mutation of TNFAIP3 [encoding a global negative regulator of the canonical nuclear factor-κB (NF-κB) pathway] in ocular adnexal MALT lymphoma; (2) IGHV1-69 was significantly overrepresented (54%) in MALT lymphoma of the salivary gland, but was not associated with mutation in any of the 17 genes investigated; and (3) MALT lymphoma lacked mutations that are frequently seen in other B-cell lymphomas characterized by constitutive NF-κB activities, including mutations in CD79B, CARD11, MYD88, TNFRSF11A, and TRAF3. Our findings show, for the first time, a significant association between biased usage of autoreactive IGHV and somatic mutation of NF-κB regulators in MALT lymphoma, arguing for their cooperation in sustaining chronic B-cell receptor signalling and driving oncogenesis in lymphoma development. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Description

Keywords

IGHV usage, MALT lymphoma, NF-κB, TNFAIP3 mutation, Biomarkers, Tumor, DNA Mutational Analysis, Eye Neoplasms, Gene Rearrangement, Gene Silencing, Genes, Immunoglobulin Heavy Chain, Genetic Predisposition to Disease, Humans, Immunoglobulin Variable Region, Lymphoma, B-Cell, Marginal Zone, Mutation, Neoplasms, Adnexal and Skin Appendage, Phenotype, Tumor Necrosis Factor alpha-Induced Protein 3

Journal Title

J Pathol

Conference Name

Journal ISSN

0022-3417
1096-9896

Volume Title

243

Publisher

Wiley
Sponsorship
Kay Kendall Leukaemia Fund (KKL582)