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Here, we performed exome\u2010wide somatic mutation analyses of bona fide autoreactive rheumatoid factor (RF)\u2010expressing memory B cells retrieved from patients with Sj\u04e7gren's syndrome (SS). The amount and repertoire of the <jats:italic>de novo<\/jats:italic> exome mutations of RF B cells were found to be essentially different from those detected in healthy donor memory B cells. In contrast to the mutation spectra of normal B cells, which appeared random and non\u2010selected, the mutations of the RF B cells were greater in number and enriched for mutations in genes also found mutated in B\u2010cell non\u2010Hodgkin lymphomas. During the study, one of the SS patients developed a diffuse large B\u2010cell lymphoma (DLBCL) out of an RF clone that was identified 2\u2009years earlier in an inflamed salivary gland biopsy. The successive oncogenic events in the RF precursor clone and the DLBCL were assessed. In conclusion, our findings of enhanced and selected genomic damage in growth\u2010regulating genes in RF memory B cells of SS patients together with the documented transformation of an RF\u2010precursor clone into DLBCL provide unique novel insight into the earliest stages of B\u2010cell derailment and lymphomagenesis. \u00a9 2022 The Authors. <jats:italic>The Journal of Pathology<\/jats:italic> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.6039","type":"journal-article","created":{"date-parts":[[2022,11,25]],"date-time":"2022-11-25T07:16:01Z","timestamp":1669360561000},"page":"264-275","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Lymphoma\u2010associated mutations in autoreactive memory B cells of patients with Sj\u00f6gren's syndrome"],"prefix":"10.1002","volume":"259","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5173-3138","authenticated-orcid":false,"given":"Richard J","family":"Bende","sequence":"first","affiliation":[{"name":"Department of Pathology, Amsterdam UMC University of Amsterdam  Amsterdam The Netherlands"},{"name":"Lymphoma and Myeloma Center (LYMMCARE)  Amsterdam The Netherlands"},{"name":"Cancer Center Amsterdam (CCA)  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda M","family":"Slot","sequence":"additional","affiliation":[{"name":"Department of Pathology, Amsterdam UMC University of Amsterdam  Amsterdam The Netherlands"},{"name":"Lymphoma and Myeloma Center (LYMMCARE)  Amsterdam The Netherlands"},{"name":"Cancer Center Amsterdam (CCA)  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark J","family":"Kwakkenbos","sequence":"additional","affiliation":[{"name":"AIMM Therapeutics  Amsterdam The 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