Analysis of p53 and Bak gene mutations in lymphoproliferative disorders developing in rheumatoid arthritis.
OBJECTIVE
Individuals affected by rheumatoid arthritis (RA) occasionally develop lymphoproliferative disorders (RA-LPD). To study the molecular changes underscoring the RA-LPD, mutations of p53 and Bak gene were analyzed in RA-LPD with (MTX-LPD) or without methotrexate treatment for RA (non-MTX-LPD).


METHODS
Histology and immunophenotype were immunohistochemically examined in 32 cases of MTX-LPD and 21 of non-MTX-LPD. Polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) followed by direct sequencing was employed to detect the mutations of p53 and Bak gene.


RESULTS
Frequency of p53 mutations in non-MTX-LPD (47.6%) was significantly higher than that in MTX-LPD (15.6%) (P < 0.05). Among the cases with non-Hodgkin's lymphoma (NHL), the largest category of RA-LPD, the frequency of p53 mutations in the non-MTX-NHL (47.6%) was significantly higher than that in the MTX-NHL (14.8%) (P < 0.05). Interval between the onset of RA and LPD development was significantly longer in LPD with p53 gene mutations (median 228 months) than that without mutations (133 months). LPD with p53 gene mutations had more advanced diseases and an unfavorable prognosis than those without mutations.


CONCLUSIONS
MTX-LPD and non-MTX-LPD show similar findings in clinical characteristics, histology, EBV positive rate, and frequency of Bak gene mutations. Whereas the non-MTX-LPD is distinct from the MTX-LPD in its significantly higher p53 mutation frequency.
Xu
Jing-Xian
JX
Department of Pathology (C3), Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Hoshida
Yoshihiko
Y
Hongyo
Tadashi
T
Sasaki
Toru
T
Miyazato
Hajime
H
Tomita
Yasuhiko
Y
Aozasa
Katsuyuki
K
D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000150:complications / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008232:Lymphoproliferative Disorders / Q000209:etiology / Q000235:genetics*; D008297:Male; D008727:Methotrexate / Q000494:pharmacology; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D011379:Prognosis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics*
C494772:BAK1 protein, human; D016159:Tumor Suppressor Protein p53; D050998:bcl-2 Homologous Antagonist-Killer Protein; D008727:Methotrexate