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

  • Original Paper
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

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.

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Abbreviations

ATL:

Adult T cell leukemia/lymphoma

DLBCL:

Diffuse large B-cell lymphoma

EBV:

Epstein–Barr virus

ISH:

In situ hybridization

RA:

Rheumatoid arthritis

RA-LPD:

Rheumatoid arthritis associated lymphoproliferative disorders

PCR-SSCP:

Polymerase chain reaction-single strand conformation polymorphism

MTX:

Methotrexate

MTX-LPD:

Methotrexate associated lymphoproliferative disorders

NHL:

Non-Hodgkin’s lymphoma

WHO:

World Health Organization

References

  • 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 48:1543–1550

    Article  PubMed  Google Scholar 

  • 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 85:718–724

    Article  CAS  PubMed  Google Scholar 

  • 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 374:733–736

    Article  CAS  PubMed  Google Scholar 

  • 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 356:215–221

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • 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 96:1691–1702

    Article  CAS  PubMed  Google Scholar 

  • 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 88:5413–5417

    Article  CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • 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 85:307–311

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • 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

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • 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 21:3637–3642

    CAS  PubMed  Google Scholar 

  • 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 58:1105–1107

    CAS  PubMed  Google Scholar 

  • 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 82:257–264

    CAS  PubMed  Google Scholar 

  • 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 108:443–449

    Article  CAS  PubMed  Google Scholar 

  • 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 69:175–183

    Article  CAS  PubMed  Google Scholar 

  • 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 75:816–821

    CAS  PubMed  Google Scholar 

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

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Google Scholar 

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

    Article  Google Scholar 

  • 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 90:4078–4091

    CAS  PubMed  Google Scholar 

  • 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 60:4328–4330

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • 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 80:493–499

    CAS  PubMed  Google Scholar 

  • 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 99:3909–3915

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • 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 35:1–39

    CAS  PubMed  Google Scholar 

  • 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 14:1943–1949

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • 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 102:11272–11277

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • 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 88:1584–1586

    Article  CAS  PubMed  Google Scholar 

  • 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 139:1259–1265

    CAS  PubMed  Google Scholar 

  • 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 89:601–609

    CAS  PubMed  Google Scholar 

  • 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 99:10025–10030

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank the following pathologists and physicians for providing clinical information: K. Taneichi, K. Shishido (Kitami Red Cross Hosp.), H. Satoh, M. Mukai (Sapporo Municipal Hosp.), M. Nagata (Tsukuba Univ.), S. Itoyama, (Saitama Medical School), A. Itsumi (Nihon Univ. Nerima Mitsugaoka Hosp.), R. Ariwa (Otsuka Metropolitan Hosp.), Y. Kurasono, M. Hara (Yokohama City Univ.), S. Toma, S. Sugii, H. Mitomi (National Sagamihara Hops.), H. Sugiura (Kawasaki Municipal Ida Hosp.), Y. Kondo, I. Okayasu (Kitasato Univ.), M. Naitoh, T. Hasegawa, K. Arai, N. Endo (Niigata Univ.), S. Furuta (National Tosei Hosp.), K. Itoh (Yugawara Kosei Hosp.), M. Itoh (Numazu Seirei Hosp.), T. Nojima, S. Sugai, H. Kawabata (Kanazawa Medical Univ.), Y. Kageyama, K. Miura (Hamamatsu Medical Univ.), M. Hayakawa (Hamamatsu Red Cross Hosp.), M. Maeda (Toyohashi Municipal Hosp.), M. Mizushima (Tajimi Prefectural Hosp.), A. Ishihara (Matsusaka Chuo Hosp.), Y. Kobashi (Tenri Hosp.), S. Ohshima, T. Ueda, H. Yoshikawa, N. Yamamoto (Osaka Univ.), M. Tsudo, Y. Arima, M. Shintaku (Osaka Red Cross Hosp,), M. Tsujimoto (Osaka Police Hosp.), T. Yamagami, T. Soma, H. Tamaki (National Osaka Minami Hosp.), M. Yaita (Kitano Hosp.), M. Yukioka (Yukioka Hosp.), S. Ishiguro, N. Araki (Center for Cancer and Cardiovascular Diseases, Osaka), K. Uda, H. Yamamoto (Saiseikai Tondabayashi Hosp.), H. Nakanishi (Kyowakai Hosp.), A. Kanamaru (Kinki Univ.), K. Maeda (NTT West Hosp.), S. Kosugi (Toyonaka Municipal Hosp.), M. Yamauchi (Sakai Municipal Hosp.), T. Tamaki, K. Iwase, M. Imakita (Izumisano Municipal Hosp.), T. Tachikawa, K. Yoshida (Kinki Chuo Hosp.), S. Yamamoto (Kansai Rosai Hosp.), H. Hashimoto, K. Saito (Univ. of Occupational and Environmental Health), Y. Iwata (Kyusyu Koseinenkin Hosp.), M Ogata, K. Kashima (Oita Univ.), and S. Yonemitsu, M. Yamaguchi (Saga Univ.).

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Authors and Affiliations

  1. Department of Pathology (C3), Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Jing-Xian Xu, Yoshihiko Hoshida, Toru Sasaki, Hajime Miyazato, Yasuhiko Tomita & Katsuyuki Aozasa

  2. Department of Radiation Biology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Tadashi Hongyo

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  1. Jing-Xian Xu
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  2. Yoshihiko Hoshida
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  3. Tadashi Hongyo
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  4. Toru Sasaki
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  5. Hajime Miyazato
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  6. Yasuhiko Tomita
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  7. Katsuyuki Aozasa
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Correspondence to Yoshihiko Hoshida.

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Supported in part by grants from the Ministry of Education, Science, Culture and Sports (15406013, 16390105, 16590277), Japan.

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Xu, JX., Hoshida, Y., Hongyo, T. et al. Analysis of p53 and Bak gene mutations in lymphoproliferative disorders developing in rheumatoid arthritis. J Cancer Res Clin Oncol 133, 125–133 (2007). https://doi.org/10.1007/s00432-006-0152-2

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  • DOI: https://doi.org/10.1007/s00432-006-0152-2

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