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A mutational analysis has been performed on post\u2010transplantation and HIV\u2010positive lymphomas, but not on other iatrogenic immunodeficiency (OII)\u2010associated LPDs mainly caused by methotrexate (MTX) to treat rheumatoid arthritis. We herein conducted next\u2010generation sequencing (NGS) to examine the genetic spectrum along with a fluorescence in\u00a0situ hybridization analysis of 9p24.1 and PD\u2010L1 expression in 37 MTX\u2010associated diffuse large B\u2010cell lymphoma (DLBCL) cases, 17 Epstein\u2013Barr virus (EBV)\u2010positive mucocutaneous ulcer (EBVMCU) cases, and 26 EBV\u2010positive DLBCL (EBV\u2009+\u2009DLBCL) cases. Targeted NGS identified 177 mutations. The mutation frequency was significantly higher in EBV<jats:sup>\u2212<\/jats:sup> MTX\u2010DLBCL than in EBV\u2010positive LPDs\/lymphomas (EBVMCU, EBV<jats:sup>+<\/jats:sup> MTX\u2010DLBCL, and EBV\u2009+\u2009DLBCL). Regrowth or resistance to spontaneous regression after MTX withdrawal was more likely in EBV<jats:sup>\u2212<\/jats:sup> MTX\u2010DLBCL than in EBV<jats:sup>+<\/jats:sup> MTX\u2010DLBCL. Therefore, accumulated gene mutations, sustained by the restored immune status in EBV<jats:sup>\u2212<\/jats:sup> MTX\u2010DLBCL, may affect clinical outcomes after MTX discontinuation. Several unique genetic findings were obtained for each category. Fewer <jats:italic>TET2\/DNMT3A<\/jats:italic> and <jats:italic>CD58<\/jats:italic> mutations in OII\u2010LPD\/lymphomas (EBVMCU and MTX\u2010DLBCL) than in EBV\u2009+\u2009DLBCL indicate that clonal hematopoiesis and an immune evasion\u2010related background contributed less to lymphomagenesis in OII\u2010LPDs. <jats:italic>MYD88<\/jats:italic><jats:sup>L265P<\/jats:sup>\/<jats:italic>CD79B<\/jats:italic><jats:sup>Y196<\/jats:sup> mutations were only detected in EBV<jats:sup>\u2212<\/jats:sup> MTX\u2010DLBCL. <jats:italic>SOCS1<\/jats:italic> mutations were significantly more frequent in EBV\u2010positive LPD\/lymphoma categories, irrespective of the immune status, than in EBV<jats:sup>\u2212<\/jats:sup> MTX\u2010DLBCL. These results reveal distinct genetic features among MTX\u2010DLBCL (EBV+\/\u2212), EBVMCU, and EBV\u2009+\u2009DLBCL.<\/jats:p>","DOI":"10.1111\/cas.70111","type":"journal-article","created":{"date-parts":[[2025,6,3]],"date-time":"2025-06-03T05:33:15Z","timestamp":1748928795000},"page":"2306-2316","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Genetic Profiling Reveals the Distinctions Among MTX\u2010Associated DLBCL, EBV\u2010Positive Mucocutaneous Ulcer, and EBV\u2009+\u2009DLBCL"],"prefix":"10.1111","volume":"116","author":[{"given":"Takumi","family":"Takahashi","sequence":"first","affiliation":[{"name":"Department of Pathology, Saitama Medical Center Saitama Medical University  Saitama Japan"},{"name":"Department of Oral and Maxillofacial Surgery, Saitama Medical Center Saitama Medical University  Saitama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keisuke","family":"Sawada","sequence":"additional","affiliation":[{"name":"Department of Pathology, Saitama Medical Center Saitama Medical University  Saitama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahisa","family":"Yamashita","sequence":"additional","affiliation":[{"name":"Department of Pathology, Saitama Medical Center Saitama Medical University  Saitama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wataru","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Pathology, Saitama Medical Center Saitama Medical University  Saitama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yosuke","family":"Iijima","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, Saitama Medical Center Saitama Medical University  Saitama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akiko","family":"Adachi","sequence":"additional","affiliation":[{"name":"Department of Diagnostic Pathology Saitama Red Cross Hospital  Saitama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Kashimura","sequence":"additional","affiliation":[{"name":"Department of Hematology Shinmatsudo Central General Hospital  Matsudo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayuki","family":"Tabayashi","sequence":"additional","affiliation":[{"name":"Department of Hematology, Saitama Medical Center Saitama Medical University  Saitama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiro","family":"Kizaki","sequence":"additional","affiliation":[{"name":"Department of Hematology, Saitama Medical Center Saitama Medical University  Saitama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Kaneko","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, Saitama Medical Center Saitama Medical University  Saitama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun\u2010ichi","family":"Tamaru","sequence":"additional","affiliation":[{"name":"Department of Pathology, Saitama Medical Center Saitama Medical University  Saitama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morihiro","family":"Higashi","sequence":"additional","affiliation":[{"name":"Department of Pathology, Saitama Medical Center Saitama Medical University  Saitama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3986-1409","authenticated-orcid":false,"given":"Shuji","family":"Momose","sequence":"additional","affiliation":[{"name":"Department of Pathology, Saitama Medical Center Saitama Medical University  Saitama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,6,3]]},"reference":[{"key":"e_1_2_11_2_1","volume-title":"Post\u2010Transplant Lymphoproliferative Disorders. 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