Genetic Profiling Reveals the Distinctions Among MTX-Associated DLBCL, EBV-Positive Mucocutaneous Ulcer, and EBV + DLBCL.

in Cancer science by 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

TLDR

  • The study examined the genetic spectrum of MTX-associated DLBCL cases and found distinct genetic features compared to EBV-positive LPDs/lymphomas.

Abstract

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 EBVMTX-DLBCL than in EBV-positive LPDs/lymphomas (EBVMCU, EBVMTX-DLBCL, and EBV + DLBCL). Regrowth or resistance to spontaneous regression after MTX withdrawal was more likely in EBVMTX-DLBCL than in EBVMTX-DLBCL. Therefore, accumulated gene mutations, sustained by the restored immune status in EBVMTX-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/CD79Bmutations were only detected in EBVMTX-DLBCL. SOCS1 mutations were significantly more frequent in EBV-positive LPD/lymphoma categories, irrespective of the immune status, than in EBVMTX-DLBCL. These results reveal distinct genetic features among MTX-DLBCL (EBV+/-), EBVMCU, and EBV + DLBCL.

Overview

  • The World Health Organization (WHO) has revised the classification system for immunodeficiency/dysregulation (IDD)-associated lymphoproliferative disorders (LPDs)/lymphomas.
  • The study aimed to investigate the genetic spectrum of MTX-associated diffuse large B-cell lymphoma (DLBCL) cases and compare it to EBV-positive mucocutaneous ulcer (EBVMCU) cases and EBV-positive DLBCL (EBV+DLBCL) cases.
  • The study used next-generation sequencing (NGS) and fluorescence in situ hybridization analysis to examine the genetic spectrum, 9p24.1, and PD-L1 expression in 80 cases, including 37 MTX-associated DLBCL, 17 EBVMCU, and 26 EBV+DLBCL cases.

Comparative Analysis & Findings

  • The study found that the mutation frequency was significantly higher in MTX-associated DLBCL than in EBV-positive LPDs/lymphomas (EBVMCU, MTX-associated DLBCL, and EBV+DLBCL).
  • The study identified unique genetic findings for each category, with fewer TET2/DNMT3A and CD58 mutations in OII-LPD/lymphomas (EBVMCU and MTX-associated DLBCL) than in EBV+DLBCL.
  • The study found that MYD88/CD79B mutations were only detected in MTX-associated DLBCL, while SOCS1 mutations were significantly more frequent in EBV-positive LPD/lymphoma categories, regardless of immune status, than in MTX-associated DLBCL.

Implications and Future Directions

  • The study's findings suggest that accumulated gene mutations, sustained by the restored immune status in MTX-associated DLBCL, may affect clinical outcomes after MTX discontinuation.
  • Future studies should investigate the clinical implications of the unique genetic features identified in this study.
  • The study's findings may also inform the development of targeted therapies for MTX-associated DLBCL and other IDD-associated LPDs/lymphomas.
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