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Hepatitis B virus infection and risk of lymphoma: results of a serological analysis within the European case–control study Epilymph

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We have recently reported from Epilymph, a multicentre case–control study of lymphoma conducted in six European countries, a significant association between NHL and self-reported history of past or present HBV infection based on questionnaire data from face-to-face interviews.


To corroborate this observation, we used the data and blood specimen from Epilymph to investigate the associations between serological indicators of HBV infection with risk of Hodgkin lymphoma, non-Hodgkin lymphoma (NHL) and specific lymphoma entities. For 1,518 cases and 1,496 controls with sufficient amount of serum or plasma, we tested HBs-antigen, anti-HBc and anti-HBs to distinguish between current or past infection and immunity by vaccination. Statistical analysis was carried out with unconditional logistic regression.


We found a positive association of a past HBV infection with multiple myeloma (MM, OR = 1.97, 95 % CL = 1.16–3.37). Non-significant associations were found between past HBV infection and B-cell chronic lymphocytic leukaemia (B-CLL, OR = 1.33, 95 % CL = 0.82–2.16) and T-cell NHL (OR = 1.59, 95 % CL = 0.65–3.90), as well as between current HBV infection and NHL (OR = 1.49, 95 % CL = 0.65–3.41), B-NHL (OR = 1.58, 95 % CL = 0.69–3.64) and diffuse large B-cell lymphoma (DLBCL, OR = 1.50, 95 % CL = 0.47–4.82). Subjects having self-reported HBV infection were serological positive in 75 % of cases and 80 % of controls. For vaccination, the corresponding figures were 49 and 54 %, respectively.


The present results support previous reports of an association between a history of HBV infection with an elevated lymphoma risk and add multiple myeloma to the list of potentially virus-associated lymphoma entities.

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  • Alexander DD, Mink PJ, Adami H-O, Chang ET, Cole P, Mandel JS, Trichopoulos D (2007) The non-Hodgkin lymphomas: a review of the epidemiologic literature. Int J Cancer 120:1–39

    Article  PubMed  Google Scholar 

  • Becker N, Deeg E, Rüdiger T, Nieters A (2005) Medical history and risk for lymphoma: results of a population-based case-control study in Germany. Eur J Cancer 41:133–142

    Article  PubMed  Google Scholar 

  • Becker N, Fortuny J, Alvaro T, Nieters A, Maynadié M, Foretova L, Staines A, Brennan P, Boffetta P, Cocco P, de Sanjosé S (2009) Medical history and risk of lymphoma: results of a European case-control study (EPILYMPH). J Cancer Res Clin Oncol 135(8):1099–1107

    Article  PubMed  Google Scholar 

  • Besson H, Brennan P, Becker N, Nieters A, De Sanjosé S, Font R, Maynadie M, Foretova L, Cocco PL, Stains A, Vornanen M, Boffetta P (2006) Tobacco smoking, alcohol drinking and non-Hodgkin’s lymphoma: a European multicenter case-control study (Epilymph). Int J Cancer 119:901–908

    Article  PubMed  CAS  Google Scholar 

  • Caillard S, Agodoa LY, Bohen EM, Abbott KC (2006) Myeloma, Hodgkin disease, and lymphoid leukemia after renal transplantation: characteristics, risk factors and prognosis. Transplantation 81:888–895

    Article  PubMed  Google Scholar 

  • Caligaris-Cappio F, Ghia P (2008) Novel insights in chronic lymphocytic leukemia: are we getting closer to understanding the pathogenesis of the disease? J Clin Oncol 26:4497–4503

    Article  PubMed  CAS  Google Scholar 

  • Chang M-H (1998) Chronic Hepatitis virus infection in children. J Gastroenterol Hepatol 13:541–548

    Article  PubMed  CAS  Google Scholar 

  • Cocco P, Piras G, Monne M, Uras A, Gabbas A, Ennas MG, Palmas A, Murineddu M, Collu S, Melis M, Rais M, Todde P, Cabras MG, Angelucci E, Massarelli G, Nieters A (2008) Risk of malignant lymphoma following viral hepatitis infection. Int J Hematol 87:474–483

    Article  PubMed  Google Scholar 

  • de Sanjose S, Benavente Y, Vajdic CM, Engels EA, Morton LM, Bracci PM, Spinelli JJ, Zheng TZ, Zhang YW, Franceschi S, Talamini R, Holly EA, Grulich AE, Cerhan JR, Hartge P, Cozen W, Boffetta P, Brennan P, Maynadie M, Cocco P, Bosch R, Foretova L, Staines A, Becker N, Nieters A (2008) Hepatitis C and non-Hodgkin lymphoma among 4784 cases and 6269 controls from the international lymphoma epidemiology consortium. Clin Gastroenterol Hepatol 6(4):451–458

    Article  PubMed  Google Scholar 

  • Engels EA, Cho ER, Jee SH (2010) Hepatitis B virus infection and risk of non-Hodgkin lymphoma in South Korea: a cohort study. Lancet Oncol 11:827–834

    Article  PubMed  Google Scholar 

  • Fortuny J, de Sanjosé S, Becker N, Maynadié M, Cocco PL, Staines A, Foretovea L, Vornanen M, Brennan P, Nieters A, Alvaro T, Boffetta P (2006) Statin use and risk of lymphoid neoplasms: results from the European case-control study EPILYMPH. Cancer Epidemiol Biomarkers Prev 15(5):921–925

    Article  PubMed  CAS  Google Scholar 

  • Franceschi S, Lise M, Trépo C, Berthillon P, Chuang S-C, Nieters A, Travis RC, Vermeulen R, Overvad K, Tjønneland A, Olsen A, Bergmann MM, Boeing H, Kaaks R, Becker N, Trichopoulou A, Lagiou P, Bamia C, Palli D, Sieri S, Panico S, Tumno R, Sacerdote C, Bueno-de-Mesquita B, Peeters PHM, Rodriguez L, Barroso LL, Dorronsoro M, Sánchez M-J, Navarro C, Barricarte A, Regnér S, Borgquist S, Melin B, Hallmans G, Khaw K-T, Wareham N, Rinaldi S, Hainaut P, Riboli E, Vineis P (2010) Infection with Hepatitis B and C viruses and risk of lymphoid malignancies in the European prospective investigation into cancer and nutrition (EPIC). Cancer Epidemiol Biomarkers Prev 20(1):208–214

    Article  PubMed  Google Scholar 

  • Grulich AE, Wan X, Law MG, Coates M, Kaldor JM (1999) Risk of cancer in people with AIDS. AIDS 13:839–843

    Article  PubMed  CAS  Google Scholar 

  • Hallek M, Bergsagel PL, Anderson KC (1998) Multiple Myeloma: increasing evidence for a multistep transformation process. Blood 91(1):3–21

    PubMed  CAS  Google Scholar 

  • Jaffé ESHN, Stein H, Vardiman JW (eds) (2001) Pathology and genetics of tumours of hematopoietic and lymphoid tissues. IARC Press, Lyon

    Google Scholar 

  • Kim JH, Bang Y-J, Park BJ, Yoo T, Kim CW, Kim T-Y, Heo DS, Lee H-S, Kim NK (2002) Hepatitis B virus infection and B-cell non-Hodgkin’s lymphoma in a hepatitis B endemic area: a case-control study. Jpn J Cancer Res 93:471–477

    Article  PubMed  CAS  Google Scholar 

  • Kinlen L (2004) Infections and immune factors in cancer: the role of epidemiology. Oncogene 23:6341–6348

    Article  PubMed  CAS  Google Scholar 

  • Klein U, Tu Y, Stolovitzky GA, Mattiolo A, Cattoretti G, Husson H, Freedmann A, Inghirami G, Cro L, Baldini L, Neri A, Califano A, Dalla-Favera R (2001) Gene expression profiling of B cell chronic lymphocytic leukemia reveals a homogeneous phenotype related to memory B cells. J Exp Med 194(11):1625–1638

    Article  PubMed  CAS  Google Scholar 

  • Kuniyoshi M, Nakamuta M, Sakai H, Enjoji M, Kinukawa N, Kotoh K, Fukutomi M, Yokota M, Nishi H, Iwamoto H, Uike N, Nishimura J, Inaba S, Maeda Y, Nawata H, Muta K (2001) Prevalence of hepatitis B or C virus infections in patients with non-Hodgkin’s lymphoma. J Gastroenterol Hepatol 16:215–219

    Article  PubMed  CAS  Google Scholar 

  • Marcucci F, Mele A, Spada E, Candidi A, Bianco E, Pulsioni A, Chionne P, Madonna E, Cotichini R, Barbui A, de Renzo A, Dore F, Iannitto E, Liso V, Martino B, Montanaro M, Pagano L, Musto P, Rapicetta M (2006) High prevalence of hepatitis B virus infection in B-cell non-Hodgkin’s lymphoma. Haematologica 91:554–557

    PubMed  Google Scholar 

  • Michalak TI (2000) Occult persistence and lymphotropism of hepadnaviral infection: insights from the woodchuck viral hepatitis model. Immunol Rev 174:98–111

    Article  PubMed  CAS  Google Scholar 

  • Murakami Y, Minami M, Daimon Y, Okanoue T (2004) Hepatitis B virus DNA in liver, serum, and peripheral blood mononuclear cells after the clearance of serum hepatitis B virus surface antigen. J Med Virol 72:203–214

    Article  PubMed  Google Scholar 

  • Murray F, Darzentas N, Hadzidimitriou A, Tobin G, Boudjogra M, Scielzo C, Laoutaris N, Karlsson K, Baran-Marzsak F, Tsaftaris A, Moreno C, Anagnostopoulos A, Caligaris-Cappio F, Vaur D, Ouzounis C, Belessi C, Ghia P, Rosenquist R, Stamatopoulos K (2008) Stereotyped patterns of somatic hypermutation in subsets of patients with chronic lymphocytic leukemia: implications for the role of antigen selection in leukemogenesis. Blood 111(3):1524–1533

    Article  PubMed  CAS  Google Scholar 

  • Nieters A, Kallinowski B, Brennan P, Ott M, Maynadié M, Benavente Y, Foretova L, Cocco PL, Staines A, Vornanen M, Whitby D, Boffetta P, Becker N, de Sanjosé S (2006) Hepatitis C and risk of lymphoma: results of the European Multicenter Case-Control Study EPILYMPH. Gastroenterology 131:1879–1886

    Article  PubMed  CAS  Google Scholar 

  • Park SC, Jeong S-H, Kim J, Han CJ, Kim YC, Choi KS, Cho JH, Lee M, Jung HH, Ki SS, Chang YH, Lee SS, Park YH, Lee KH (2008) High prevalence of Hepatitis virus infection in patients with B-cell non-Hodgkin’s lymphoma in Korea. J Med Virol 80:960–966

    Article  PubMed  CAS  Google Scholar 

  • Parkin DM, Bray FI, Devesa SS (2001) Cancer burden in the year 2000. The global picture. Eur J Cancer 37:S4–S66

    Article  PubMed  Google Scholar 

  • Quinlan SC, Morton LM, Pfeiffer RM, Anderson LA, Landgren O, Warren JL, Engels EA (2010) Increased risk for lymphoid and myeloid neoplasms in elderly solid-organ transplant recipients. Cancer Epidemiol Biomarkers Prev 19:1229–1237

    Article  PubMed  CAS  Google Scholar 

  • Raimondo G, Allain J-P, Brunetto MR, Buendia M-A, Chen D-S, Colombo M, Craxí A, Donato F, Ferrari C, Gaeta GB, Gerlich WH, Levrero M, Locarnini S, Michalak T, Mondelli MU, Pawlotsky J-M, Pollicino T, Prati D, Pueti M, Samuel D, Shouval D, Smedile A, Squadrito G, Trépo C, Villa E, Will H, Zanetti AR, Zoulim F (2008) Statements from the Taormina expert meeting on occult hepatitis B virus infection. J Hepatol 49:652–657

    Article  PubMed  Google Scholar 

  • Rehermann B, Ferrari C, Pasquinelli C, Chisari FV (1996) The hepatitis B virus persists for decades after patients′ recovery from acute viral hepatitis despite active maintenance of a cytotoxic T-lymphocyte response. Nat Med 10:1104–1108

    Google Scholar 

  • Shepard CW, Simard EP, Finelli L, Fiore AE, Bell BP (2006) Hepatitis B virus infection: epidemiology and vaccination. Epidem Rev 28:112–125

    Article  Google Scholar 

  • Suarez F, Lortholary O, Hermine O, Lecuit M (2006) Infection-associated lymphomas derived from marginal zone B cells: a model of antigen-driven lymphoproliferation. Blood 107:3034–3044

    Article  PubMed  CAS  Google Scholar 

  • Wang F, Xu R, Han B, Shi Y, Luo H, Jiang W, Lin T, Huang H, Xia Z, Guan Z (2007) High incidence of hepatitis B virus infection in B-cell subtype non-Hodgkin lymphoma compared with other cancers. Cancer 109:1360–1364

    Article  PubMed  Google Scholar 

  • Yood UM, Quesenberry CB, Guo D, Caldwell G, Wells K, Shan J, Sanders L, Skovron ML, Iloeje U, Manos MM (2007) Incidence of non-Hodgkin’s lymphoma among individuals with chronic hepatitis B virus infection. Hepatology 46:107–112

    Article  CAS  Google Scholar 

  • Zenz T, Mertens D, Küppers R, Döhner H, Stilgenbauer S (2010) From pathogenesis to treatment of chronic lymphocytic leukaemia. Nat Rev Cancer 10:37–50

    PubMed  CAS  Google Scholar 

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We are indebted to Sabine Holzmeier (German Cancer Research Center, Heidelberg) who performed data management and assisted data analysis, and Ulrike von Seydlitz-Kurzbach, Johannes Schnitzler and Theron Johnson who assisted lab analysis. Theron Johnson conducted additionally a linguistic editing of the manuscript. Epilymph was supported by: (1) the EC 5th Framework Program Quality of Life grant No. QLK4-CT-2000-00422; (2) La Fondation de France, no 1999 0084 71 (France); (3) the Federal Office for Radiation Protection grants No. StSch4261 and StSch4420 (Germany); (4) the Health Research Board, Ireland; (5) Compagnia di San Paolo di Torino, Programma Oncologia 2001 (Italy); (6) Agència de Gestió d’Ajuts Universitaris i de Recerca Generalitat de Catalunya (AGAUR 2009SGR1465) and the Spanish Ministry of Health grants FIS: 11/01810 and CIBERESP (06/02/0073) (Spain). This serological analysis was funded by the German Cancer Aid (109034).

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Becker, N., Schnitzler, P., Boffetta, P. et al. Hepatitis B virus infection and risk of lymphoma: results of a serological analysis within the European case–control study Epilymph. J Cancer Res Clin Oncol 138, 1993–2001 (2012).

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