Epstein-Barr virus infection and gene promoter hypermethylation in rheumatoid arthritis patients with methotrexate-associated B cell lymphoproliferative disorders.

Abstract

We analyzed CpG-island hypermethylation status in 12 genes of paraffin-embedded tissues from 38 rheumatoid arthritis (RA) patients with methotrexate (MTX)-associated large B cell lymphoproliferative disorder (BLPD), 11 RA patients with non-MTX-associated BLPD (non-MTX-BLPD), 22 controls with diffuse large B cell lymphoma (DLBCL), and 10 controls with Epstein-Barr virus (EBV)+ DLBCL. Among them, tumor cells from EBV+ MTX-BLPD patients and control EBV+ DLBCL patients had significantly lower median incidence of CpG island methylator phenotype (CIMP) than those from non-MTX-BLPD and control DLBCL groups (2.3 and 1.7 vs. 4.3 and 4.4; P < 0.01 for each). In the MTX-BLPD group, EBV+ patients showed lower median CIMP than EBV- patients (2.3 vs. 3.2); they also had significantly lower hypermethylation incidence in four apoptosis-related genes, especially death-associated protein kinase (14 vs. 55 %), higher incidence of massive tumor necrosis (86 vs. 27 %), and lower BCL2 protein expression (19 vs. 86 %) than did the control DLBCL group (P < 0.01 for all). In all clinical stages, EBV+ MTX-BLPD patients had better prognoses than the EBV- MTX-BLPD (P = 0.011), non-MTX-BLPD (P = 0.002), and control DLBCL groups (P = 0.015). MTX-BLPD patients without hypermethylated RAS-associated domain family-1A (RASSF1A) or O 6 -methyl guanine-DNA methyltransferase (MGMT) had significantly better prognosis than those with hypermethylation of those genes (P = 0.033). We conclude that in RA patients with MTX-BLPD, EBV infection is associated with a lower incidence of CIMP, apoptosis-related gene hypermethylation, and BCL2 expression, which can induce tumor regression by MTX withdrawal and lead to better prognoses.

• Authors: Kozue Ejima-Yamada, Yumi Oshiro, Seiichi Okamura, Tomoaki Fujisaki, Yasuhito Mihashi, Kazuo Tamura, Tomoko Fukushige, Masaru Kojima, Kazutoshi Shibuya, Morishige Takeshita
• Journal: Virchows Archiv : an international journal of pathology (Virchows Arch) Vol. 470 Issue 2 Pg. 205-215 (Feb 2017) ISSN: 1432-2307 [Electronic] Germany
• PMID: 27864689 (Publication Type: Journal Article)

Chemical References

• Antirheumatic Agents
• Genetic Markers
• Methotrexate

Topics

• Adult
• Aged
• Aged, 80 and over
• Antirheumatic Agents (adverse effects, therapeutic use)
• Arthritis, Rheumatoid (complications, drug therapy, genetics, virology)
• Case-Control Studies
• CpG Islands (genetics)
• DNA Methylation
• Epstein-Barr Virus Infections (complications, genetics)
• Female
• Genetic Markers
• Humans
• Lymphoma, Large B-Cell, Diffuse (genetics, virology)
• Lymphoproliferative Disorders (chemically induced, genetics, virology)
• Male
• Methotrexate (adverse effects, therapeutic use)
• Middle Aged
• Promoter Regions, Genetic
• Treatment Outcome