{"title":"mtx相关性DLBCL、EBV阳性粘膜皮肤溃疡和EBV + DLBCL的基因分析差异","authors":"Takumi Takahashi, Keisuke Sawada, Takahisa Yamashita, Wataru Yamamoto, Yosuke Iijima, Akiko Adachi, Makoto Kashimura, Takayuki Tabayashi, Masahiro Kizaki, Takahiro Kaneko, Jun-Ichi Tamaru, Morihiro Higashi, Shuji Momose","doi":"10.1111/cas.70111","DOIUrl":null,"url":null,"abstract":"<p><p>The WHO recently changed the outline of immunodeficiency/dysregulation (IDD)-associated lymphoproliferative disorders (LPDs)/lymphomas from underlying IDD settings to an overarching framework and accommodates commonalities in histology, the involvement of various oncogenic viruses, and specific clinical/therapeutic consequences. A mutational analysis has been performed on post-transplantation and HIV-positive lymphomas, but not on other iatrogenic immunodeficiency (OII)-associated LPDs mainly caused by methotrexate (MTX) to treat rheumatoid arthritis. We herein conducted next-generation sequencing (NGS) to examine the genetic spectrum along with a fluorescence in situ hybridization analysis of 9p24.1 and PD-L1 expression in 37 MTX-associated diffuse large B-cell lymphoma (DLBCL) cases, 17 Epstein-Barr virus (EBV)-positive mucocutaneous ulcer (EBVMCU) cases, and 26 EBV-positive DLBCL (EBV + DLBCL) cases. Targeted NGS identified 177 mutations. The mutation frequency was significantly higher in EBV<sup>-</sup> MTX-DLBCL than in EBV-positive LPDs/lymphomas (EBVMCU, EBV<sup>+</sup> MTX-DLBCL, and EBV + DLBCL). Regrowth or resistance to spontaneous regression after MTX withdrawal was more likely in EBV<sup>-</sup> MTX-DLBCL than in EBV<sup>+</sup> MTX-DLBCL. Therefore, accumulated gene mutations, sustained by the restored immune status in EBV<sup>-</sup> MTX-DLBCL, may affect clinical outcomes after MTX discontinuation. Several unique genetic findings were obtained for each category. Fewer TET2/DNMT3A and CD58 mutations in OII-LPD/lymphomas (EBVMCU and MTX-DLBCL) than in EBV + DLBCL indicate that clonal hematopoiesis and an immune evasion-related background contributed less to lymphomagenesis in OII-LPDs. MYD88<sup>L265P</sup>/CD79B<sup>Y196</sup> mutations were only detected in EBV<sup>-</sup> MTX-DLBCL. SOCS1 mutations were significantly more frequent in EBV-positive LPD/lymphoma categories, irrespective of the immune status, than in EBV<sup>-</sup> MTX-DLBCL. These results reveal distinct genetic features among MTX-DLBCL (EBV+/-), EBVMCU, and EBV + DLBCL.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7000,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Genetic Profiling Reveals the Distinctions Among MTX-Associated DLBCL, EBV-Positive Mucocutaneous Ulcer, and EBV + DLBCL.\",\"authors\":\"Takumi Takahashi, Keisuke Sawada, Takahisa Yamashita, Wataru Yamamoto, Yosuke Iijima, Akiko Adachi, Makoto Kashimura, Takayuki Tabayashi, Masahiro Kizaki, Takahiro Kaneko, Jun-Ichi Tamaru, Morihiro Higashi, Shuji Momose\",\"doi\":\"10.1111/cas.70111\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>The WHO recently changed the outline of immunodeficiency/dysregulation (IDD)-associated lymphoproliferative disorders (LPDs)/lymphomas from underlying IDD settings to an overarching framework and accommodates commonalities in histology, the involvement of various oncogenic viruses, and specific clinical/therapeutic consequences. A mutational analysis has been performed on post-transplantation and HIV-positive lymphomas, but not on other iatrogenic immunodeficiency (OII)-associated LPDs mainly caused by methotrexate (MTX) to treat rheumatoid arthritis. We herein conducted next-generation sequencing (NGS) to examine the genetic spectrum along with a fluorescence in situ hybridization analysis of 9p24.1 and PD-L1 expression in 37 MTX-associated diffuse large B-cell lymphoma (DLBCL) cases, 17 Epstein-Barr virus (EBV)-positive mucocutaneous ulcer (EBVMCU) cases, and 26 EBV-positive DLBCL (EBV + DLBCL) cases. Targeted NGS identified 177 mutations. The mutation frequency was significantly higher in EBV<sup>-</sup> MTX-DLBCL than in EBV-positive LPDs/lymphomas (EBVMCU, EBV<sup>+</sup> MTX-DLBCL, and EBV + DLBCL). Regrowth or resistance to spontaneous regression after MTX withdrawal was more likely in EBV<sup>-</sup> MTX-DLBCL than in EBV<sup>+</sup> MTX-DLBCL. Therefore, accumulated gene mutations, sustained by the restored immune status in EBV<sup>-</sup> MTX-DLBCL, may affect clinical outcomes after MTX discontinuation. Several unique genetic findings were obtained for each category. Fewer TET2/DNMT3A and CD58 mutations in OII-LPD/lymphomas (EBVMCU and MTX-DLBCL) than in EBV + DLBCL indicate that clonal hematopoiesis and an immune evasion-related background contributed less to lymphomagenesis in OII-LPDs. MYD88<sup>L265P</sup>/CD79B<sup>Y196</sup> mutations were only detected in EBV<sup>-</sup> MTX-DLBCL. SOCS1 mutations were significantly more frequent in EBV-positive LPD/lymphoma categories, irrespective of the immune status, than in EBV<sup>-</sup> MTX-DLBCL. These results reveal distinct genetic features among MTX-DLBCL (EBV+/-), EBVMCU, and EBV + DLBCL.</p>\",\"PeriodicalId\":48943,\"journal\":{\"name\":\"Cancer Science\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":5.7000,\"publicationDate\":\"2025-06-03\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cancer Science\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1111/cas.70111\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"Medicine\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Science","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1111/cas.70111","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"Medicine","Score":null,"Total":0}
Genetic Profiling Reveals the Distinctions Among MTX-Associated DLBCL, EBV-Positive Mucocutaneous Ulcer, and EBV + DLBCL.
The WHO recently changed the outline of immunodeficiency/dysregulation (IDD)-associated lymphoproliferative disorders (LPDs)/lymphomas from underlying IDD settings to an overarching framework and accommodates commonalities in histology, the involvement of various oncogenic viruses, and specific clinical/therapeutic consequences. A mutational analysis has been performed on post-transplantation and HIV-positive lymphomas, but not on other iatrogenic immunodeficiency (OII)-associated LPDs mainly caused by methotrexate (MTX) to treat rheumatoid arthritis. We herein conducted next-generation sequencing (NGS) to examine the genetic spectrum along with a fluorescence in situ hybridization analysis of 9p24.1 and PD-L1 expression in 37 MTX-associated diffuse large B-cell lymphoma (DLBCL) cases, 17 Epstein-Barr virus (EBV)-positive mucocutaneous ulcer (EBVMCU) cases, and 26 EBV-positive DLBCL (EBV + DLBCL) cases. Targeted NGS identified 177 mutations. The mutation frequency was significantly higher in EBV- MTX-DLBCL than in EBV-positive LPDs/lymphomas (EBVMCU, EBV+ MTX-DLBCL, and EBV + DLBCL). Regrowth or resistance to spontaneous regression after MTX withdrawal was more likely in EBV- MTX-DLBCL than in EBV+ MTX-DLBCL. Therefore, accumulated gene mutations, sustained by the restored immune status in EBV- MTX-DLBCL, may affect clinical outcomes after MTX discontinuation. Several unique genetic findings were obtained for each category. Fewer TET2/DNMT3A and CD58 mutations in OII-LPD/lymphomas (EBVMCU and MTX-DLBCL) than in EBV + DLBCL indicate that clonal hematopoiesis and an immune evasion-related background contributed less to lymphomagenesis in OII-LPDs. MYD88L265P/CD79BY196 mutations were only detected in EBV- MTX-DLBCL. SOCS1 mutations were significantly more frequent in EBV-positive LPD/lymphoma categories, irrespective of the immune status, than in EBV- MTX-DLBCL. These results reveal distinct genetic features among MTX-DLBCL (EBV+/-), EBVMCU, and EBV + DLBCL.
期刊介绍：
Cancer Science (formerly Japanese Journal of Cancer Research) is a monthly publication of the Japanese Cancer Association. First published in 1907, the Journal continues to publish original articles, editorials, and letters to the editor, describing original research in the fields of basic, translational and clinical cancer research. The Journal also accepts reports and case reports.
Cancer Science aims to present highly significant and timely findings that have a significant clinical impact on oncologists or that may alter the disease concept of a tumor. The Journal will not publish case reports that describe a rare tumor or condition without new findings to be added to previous reports; combination of different tumors without new suggestive findings for oncological research; remarkable effect of already known treatments without suggestive data to explain the exceptional result. Review articles may also be published.
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