Pre-diagnostic blood immune markers, incidence and progression of B-cell lymphoma and multiple myeloma: Univariate and functionally informed multivariate analyses

Roel Vermeulen*, Fatemeh Saberi Hosnijeh, Barbara Bodinier, Lutzen Portengen, Benoit Liquet, Javiera Garrido-Manriquez, Henk Lokhorst, Ingvar A. Bergdahl, Soterios A. Kyrtopoulos, Ann-Sofie Johansson, Panagiotis Georgiadis, Beatrice Melin, Domenico Palli, Vittorio Krogh, Salvatore Panico, Carlotta Sacerdote, Rosario Tumino, Paolo Vineis, Raphaele Castagne, Marc Chadeau-HyamMaria Botsivali, Aristotelis Chatziioannou, Ioannis Valavanis, Jos C. S. Kleinjans, Theo M. C. M. de Kok, Hector C. Keun, Toby J. Athersuch, Rachel Kelly, Per Lenner, Goran Hallmans, Euripides G. Stephanou, Antonis Myridakis, Manolis Kogevinas, Lucia Fazzo, Marco De Santis, Pietro Comba, Benedetta Bendinelli, Hannu Kiviranta, Panu Rantakokko, Riikka Airaksinen, Paivi Ruokojarvi, Mark Gilthorpe, Sarah Fleming, Thomas Fleming, Yu-Kang Tu, Thomas Lundh, Kuo-Liong Chien, Wei J. Chen, Wen-Chung Lee, Chuhsing Kate Hsiao, EnviroGenomarkers Consortium

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

12 Citations (Web of Science)


Recent prospective studies have shown that dysregulation of the immune system may precede the development of B-cell lymphomas (BCL) in immunocompetent individuals. However, to date, the studies were restricted to a few immune markers, which were considered separately. Using a nested case-control study within two European prospective cohorts, we measured plasma levels of 28 immune markers in samples collected a median of 6 years before diagnosis (range 2.01-15.97) in 268 incident cases of BCL (including multiple myeloma [ MM]) and matched controls. Linear mixed models and partial least square analyses were used to analyze the association between levels of immune marker and the incidence of BCL and its main histological subtypes and to investigate potential biomarkers predictive of the time to diagnosis. Linear mixed model analyses identified associations linking lower levels of fibroblast growth factor-2 (FGF-2 p = 7.2 x 10(-4)) and transforming growth factor alpha (TGF-alpha, p = 6.5 x 10(-5)) and BCL incidence. Analyses stratified by histological subtypes identified inverse associations for MM subtype including FGF-2 (p = 7.8 x 10(-7)), TGF-alpha (p = 4.08 x 10(-5)), fractalkine (p = 1.12 x 10(-3)), monocyte chemotactic protein-3 (p = 1.36 x 10(-4)), macrophage inflammatory protein 1-alpha (p = 4.6 x 10(-4)) and vascular endothelial growth factor (p = 4.23 x 10(-5)). Our results also provided marginal support for already reported associations between chemokines and diffuse large BCL (DLBCL) and cytokines and chronic lymphocytic leukemia (CLL). Case-only analyses showed that Granulocyte-macrophage colony stimulating factor levels were consistently higher closer to diagnosis, which provides further evidence of its role in tumor progression. In conclusion, our study suggests a role of growth-factors in the incidence of MM and of chemokine and cytokine regulation in DLBCL and CLL. What's new? B-cell lymphomas (BCL) are frequent in immunocompromised individuals, but most BCL cases are thought to occur as a consequence of minor immune perturbations in otherwise immunocompetent individuals. Here the authors prospectively examined a panel of immune markers in the blood from 268 patients afflicted with BCL and paired controls. The data uncover a functional role for growth factors (i.e. FGF-2, TGF-alpha) in the incidence and progression of multiple myeloma, a BCL subtype, and underscore the importance of chemokine and cytokine regulation in diffuse large B-cell lymphoma and chronic lymphocytic leukemia.
Original languageEnglish
Pages (from-to)1335-1347
Number of pages13
JournalInternational Journal of Cancer
Issue number6
Publication statusPublished - 15 Sept 2018


  • lymphoma
  • multiple myeloma
  • cytokine
  • prospective cohort
  • mixed-effect modeling
  • multivariate models
  • time to diagnosis

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