title: 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 O6-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.affiliation: Division of Medical Oncology, Hematology and Infectious Disease, Department of Pathology, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan.|Department of Pathology, Toho University Medical Center, Omori-nichi, Ota-ku, Tokyo, 143-8541, Japan.
authors.forename: Kozue
authors.initials: K
authors.lastname: Ejima-Yamada
authors.affiliation: Pathological Laboratory, Matsuyama Red Cross Hospital, 1 Bunkyo-cho, Matsuyama, 790-8524, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Oshiro
authors.affiliation: Department of Hematology, Clinical Research Center, National Hospital Organization Kyushu Medical Center, 1-8-1 Jigyohama, Chuo-ku, Fukuoka, 810-8563, Japan.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Okamura
authors.affiliation: Department of Hematology, Matsuyama Red Cross Hospital, 1 Bunkyo-cho, Matsuyama, 790-8524, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Fujisaki
authors.affiliation: Division of Medical Oncology, Hematology and Infectious Disease, Department of Pathology, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Mihashi
authors.affiliation: Division of Medical Oncology, Hematology and Infectious Disease, Department of Internal Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Tamura
authors.affiliation: Division of Medical Oncology, Hematology and Infectious Disease, Department of Pathology, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Fukushige
authors.affiliation: Department of Pathology, Dokkyo Medical University, 880 Kitakobayashi, Mibu-cho, Tochigi, 321-0293, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Kojima
authors.affiliation: Department of Pathology, Toho University Medical Center, Omori-nichi, Ota-ku, Tokyo, 143-8541, Japan.
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Shibuya
authors.affiliation: Division of Medical Oncology, Hematology and Infectious Disease, Department of Pathology, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan. m-take@adm.fukuoka-u.ac.jp.
authors.forename: Morishige
authors.initials: M
authors.lastname: Takeshita
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018501:Antirheumatic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000821:virology; D016022:Case-Control Studies; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D020031:Epstein-Barr Virus Infections / Q000150:complications / Q000235:genetics*; D005260:Female; D005819:Genetic Markers; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000821:virology; D008232:Lymphoproliferative Disorders / Q000139:chemically induced* / Q000235:genetics / Q000821:virology; D008297:Male; D008727:Methotrexate / Q000009:adverse effects* / Q000627:therapeutic use; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D016896:Treatment Outcome
chemical_list: D018501:Antirheumatic Agents; D005819:Genetic Markers; D008727:Methotrexate
keywords: B cell lymphoproliferative disorder; CpG islands; DNA methylation; Epstein–Barr virus; Methotrexate; Rheumatoid arthritis