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Journal of Cancer Research and Clinical Oncology

Erschienen in:

01.02.2007 | Original Paper

Analysis of p53 and Bak gene mutations in lymphoproliferative disorders developing in rheumatoid arthritis

verfasst von: Jing-Xian Xu, Yoshihiko Hoshida, Tadashi Hongyo, Toru Sasaki, Hajime Miyazato, Yasuhiko Tomita, Katsuyuki Aozasa

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 2/2007

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Abstract

Purpose

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.

Baecklund E, Sundstrom C, Ekbom A, Catrina AI, Biberfeld P, Feltelius N, Klareskog L (2003) Lymphoma subtypes in patients with rheumatoid arthritis: increased proportion of diffuse large B cell lymphoma. Arthritis Rheum 48:1543–1550CrossRefPubMed

Chen PM, Chiou TJ, Hsieh RK, Fan FS, Chu CJ, Lin CZ, Chiang H, Yen CC, Wang WS, Liu JH (1999) p53 gene mutations and rearrangements in non-Hodgkin’s lymphoma. Cancer 85:718–724CrossRefPubMed

Chittenden T, Harrington EA, O’Connor R, Flemington C, Lutz RJ, Evan GI, Guild BC (1995) Induction of apoptosis by the Bcl-2 homologue Bak. Nature 374:733–736CrossRefPubMed

Donehower LA, Harvey M, Slagle BL, McArthur MJ, Montgomery CA Jr, Butel JS, Bradley A (1992) Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumors. Nature 356:215–221CrossRefPubMed

Edwards RH, Raab-Traub N (1994) Alterations of the p53 gene in Epstein–Barr virus-associated immunodeficiency-related lymphoma. J Virol 68:1309–1315PubMed

Ellman MH, Hurwitz H, Thomas C, Kozloff M (1991) Lymphoma developing in a patient with rheumatoid arthritis taking low dose weekly methotrexate. J Rheumatol 18:1741–1743PubMed

Feng WH, Cohen JI, Fischer S, Li L, Sneller M, Goldbach-Mansky R, Raab-Traub N, Delecluse HJ, Kenney SC (2004) Reactivation of latent Epstein–Barr virus by methotrexate. A potential contributor to methotrexate-associated lymphomas. J Natl Cancer Inst 96:1691–1702PubMedCrossRef

Gaidano G, Ballerini P, Gong JZ, Inghirami G, Neri A, Newcomb EW, Magrath IT, Knowles DM, Dalla-Favera R (1991) p53 mutations in human lymphoid malignancies association with Burkitt lymphoma and chronic lymphocytic leukemia. Proc Natl Acad Sci USA 88:5413–5417CrossRefPubMed

Gaidano G, Carbone A, Dalla-Favera R (1998) Genetic basis of acquired immunodeficiency syndrome-related lymphomagenesis. J Natl Cancer Inst Monogr 23:95–100PubMed

Georgescu L, Paget SA (1999) Lymphoma in patients with rheumatoid arthritis: what is the evidence of a link with methotrexate? Drug Saf 20:475–487CrossRefPubMed

Gridley G, McLaughlin JK, Ekbom A, Klareskog L, Adami HO, Hacker DG, Hoover R, Fraumeni JF Jr (1993) Incidence of cancer among patients with rheumatoid arthritis. J Natl Cancer Inst 85:307–311PubMed

Hanna N, Fidler IJ (1980) Role of natural killer cells in the destruction of circulating tumor emboli. J Natl Cancer Inst 65:801–809PubMed

Harris NL, Swerdlow SH (2001) Methotrexate-associated lymphoproliferative disorders. In: Jaffe ES, Harris NL and Stein H et al (eds) Pathology and Genetics, Tumours of Haematopoietic and Lymphoid Tissues, World Health Organization Classification of Tumours. IARC Press, Lyon pp 270–271

Hollstein M, Sidransky D, Vogelstein B, Harris SR (1991) p53 mutations in human cancers. Science 253:49–53CrossRefPubMed

Hongyo T, Buzard GS, Calvert RJ, Weghorst CM (1993) ‘Cold SSCP’: a simple, rapid and non-radioactive method for optimized single strand conformation polymorphism analyses. Nucleic Acids Res 21:3637–3642PubMed

Hongyo T, Kurooka M, Taniguchi E, Iuchi K, Nakajima Y, Aozasa K, Nomura T (1998) Frequent p53 mutations at dipyrimidine sites in patients with pyothorax-associated lymphoma. Cancer Res 58:1105–1107PubMed

Hoshida Y, Hongyo T, Nakatsuka S, Nishiu M, Takakuwa T, Tomita Y, Nomura T, Aozasa K (2002) Gene mutations in lymphoproliferative disorders of T and NK/T cell phenotypes developing in renal transplant patients. Lab Invest 82:257–264PubMed

Hoshida Y, Tomita Y, Zhiming D, Yamauchi A, Nakatsuka S, Kurasono Y, Arima Y, Tsudo M, Shintaku M, Aozasa K (2004) Lymphoproliferative disorders in autoimmune diseases in Japan: analysis of clinicopathological features and Epstein–Barr virus infection. Int J Cancer 108:443–449CrossRefPubMed

Hoshida Y, Hongyo T, Xu JX, Sasaki T, Tomita Y, Nomura T, Aozasa K (2005) TP53 gene mutation is an unfavorable prognostic factor for malignant lymphomas in autoimmune disease. Oncology 69:175–183CrossRefPubMed

Hsu S-M, Raine L, Fanger H (1981) The use of antiavidin antibody and avidin–biotin–peroxidase complex in immuno-peroxidase technics. Am J Clin Pathol 75:816–821PubMed

Imamura J, Miyoshi I, Koeffler HP (2002) p53 in hematologic malignancy. Blood 84:2412–2421

Isomaki HA, Hakulinen T, Joutsenlahti U (1978) Excess risk of lymphomas, leukemia and myeloma in patients with rheumatoid arthritis. J Chronic Dis 31:691–696CrossRefPubMed

Jaffe ES, Harris NL, Stein H, Vardiman JW (2001) Pathology and genetics, tumours of haematopoietic and lymphoid tissues, World Health Organization classification of tumours. IARC Press, Lyon

Kaplan EL, Meier P (1958) Non-parametric estimation from incomplete observations. J Amer Statist Assoc 53:457–481CrossRef

Koduru PR, Raju K, Vadmal V, Menezes G, Shah S, Susin M, Kolitz J, Broome JD (1997) Correlation between mutation in P53, p53 expression, cytogenetics, histologic type, and survival in patients with B-cell non-Hodgkin’s lymphoma. Blood 90:4078–4091PubMed

Kondo S, Shinomura Y, Miyazaki Y, Kiyohara T, Tsutsui S, Kitamura S, Nagasawa Y, Nakahara M, Kanayama S, Matsuzawa Y (2000) Mutations of the Bak gene in human gastric and colorectal cancers. Cancer Res 60:4328–4330PubMed

Levine AJ, Momand J, Finley CA (1991) The p53 tumor suppressor gene. Nature 351:453–456CrossRefPubMed

Li T, Hongyo T, Syaifudin M, Nomura T, Dong Z, Shingu N, Kojya S, Nakatsuka S, Aozasa K (2000) Mutations of the p53 gene in nasal NK/T-cell lymphoma. Lab Invest 80:493–499PubMed

Mariette X, Cazals-Hatem D, Warszawki J, Liote F, Balandraud N, Sibilia J (2002) Investigators of the Club Rhumatismes et Inflammation: Lymphomas in rheumatoid arthritis patients treated with methotrexate: a 3-year prospective study in France. Blood 99:3909–3915CrossRefPubMed

Mellemkjaer L, Linet MS, Gridley G, Frisch M, Moller H, Olsen JH (1996) Rheumatoid arthritis and cancer risk. Eur J Cancer 32A:1753–1757CrossRefPubMed

Newcomb EW (1995) P53 gene mutations in lymphoid diseases and their possible relevance to drug resistance. Leuk Lymphoma 17:211–221PubMed

Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, Mantel N, McPherson K, Peto J, Smith PG (1977) Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. Analysis and examples. Br J Cancer 35:1–39PubMed

Salloum E, Cooper DL, Howe G, Lacy J, Tallini G, Crouch J, Schultz M, Murren J (1996) Spontaneous regression of lymphoproliferative disorders in patients treated with methotrexate for rheumatoid arthritis and other rheumatic diseases. J Clin Oncol 14:1943–1949PubMed

Symmons DP (1985) Neoplasms of the immune system in rheumatic arthritis. Am J Med 78:22–28CrossRefPubMed

Takeuchi O, Fisher J, Suh H, Harada H, Malynn BA, Korsmeyer S (2005) Essential role of BAX, BAK in B cell homeostasis and prevention of autoimmune disease. Proc Natl Acad Sci USA 102:11272–11277CrossRefPubMed

Thomas E, Brewster DH, Black RJ, Macfarlane GJ (2000) Risk of malignancy among patients with rheumatic conditions. Int J Cancer 88:497–502CrossRefPubMed

Wani KM, Huilgol NG, Hongyo T, Shah K, Chatterjee N, Nair CK, Nomura T (2003) Genetic alterations in the coding region of the Bak gene in uterine cervical cancinoma. Br J Cancer 88:1584–1586CrossRefPubMed

Weiss LM, Chen Y-Y, Liu XF, Shibata D (1991) Epstein–Barr virus and Hodgkin’s disease: a correlative in situ hybridization and polymerase chain reaction study. Am J Pathol 139:1259–1265PubMed

Wilson WH, Teruya-Feldstein J, Fest T, Harris C, Steinberg SM, Jaffe ES, Raffeld M (1997) Relationship of p53, bcl-2, and tumor proliferation to clinical drug resistance in non-Hodgkin’s lymphomas. Blood 89:601–609PubMed

Yamanishi Y, Boyle DL, Rosengren S, Green DR, Zvaifler NJ, Firestein GS (2002) Regional analysis of p53 mutations in rheumatoid arthritis synovium. Proc Natl Acad Sci USA 99:10025–10030CrossRefPubMed

Titel: Analysis of p53 and Bak gene mutations in lymphoproliferative disorders developing in rheumatoid arthritis
verfasst von: Jing-Xian Xu
Yoshihiko Hoshida
Tadashi Hongyo
Toru Sasaki
Hajime Miyazato
Yasuhiko Tomita
Katsuyuki Aozasa
Publikationsdatum: 01.02.2007
Verlag: Springer-Verlag
Erschienen in: Journal of Cancer Research and Clinical Oncology / Ausgabe 2/2007
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-006-0152-2

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Analysis of p53 and Bak gene mutations in lymphoproliferative disorders developing in rheumatoid arthritis