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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\u201034 (binds to the carbohydrate I\/i antigens) and inactivating mutation of <jats:italic>TNFAIP3<\/jats:italic> [encoding a global negative regulator of the canonical nuclear factor\u2010\u03baB (NF\u2010\u03baB) pathway] in ocular adnexal MALT lymphoma; (2) IGHV1\u201069 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\u2010cell lymphomas characterized by constitutive NF\u2010\u03baB activities, including mutations in <jats:italic>CD79B<\/jats:italic>, <jats:italic>CARD11<\/jats:italic>, <jats:italic>MYD88<\/jats:italic>, <jats:italic>TNFRSF11A<\/jats:italic>, and <jats:italic>TRAF3<\/jats:italic>. Our findings show, for the first time, a significant association between biased usage of autoreactive IGHV and somatic mutation of NF\u2010\u03baB regulators in MALT lymphoma, arguing for their cooperation in sustaining chronic B\u2010cell receptor signalling and driving oncogenesis in lymphoma development. Copyright \u00a9 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.4933","type":"journal-article","created":{"date-parts":[[2017,7,6]],"date-time":"2017-07-06T09:06:38Z","timestamp":1499331998000},"page":"3-8","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Significant association between <i>TNFAIP3<\/i> inactivation and biased immunoglobulin heavy chain variable region 4\u201034 usage in mucosa\u2010associated lymphoid tissue lymphoma"],"prefix":"10.1002","volume":"243","author":[{"given":"Sarah","family":"Moody","sequence":"first","affiliation":[{"name":"Division of Cellular and Molecular Pathology, Department of Pathology University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leire","family":"Escudero\u2010Ibarz","sequence":"additional","affiliation":[{"name":"Division of Cellular and Molecular Pathology, Department of Pathology University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Cellular and Molecular Pathology, Department of Pathology University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Clipson","sequence":"additional","affiliation":[{"name":"Division of Cellular and Molecular Pathology, Department of Pathology University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eguzkine","family":"Ochoa Ruiz","sequence":"additional","affiliation":[{"name":"Division of Cellular and Molecular Pathology, Department of Pathology University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah","family":"Dunn\u2010Walters","sequence":"additional","affiliation":[{"name":"Division of Infection, Immunity and Inflammatory Disease King's College London Faculty of Life Sciences &amp; 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