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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.

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 prior to diagnosis (range, 2.01-15.97) in 268 incident cases of BCL (including multiple myeloma) 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 modelIrrespective of the model, our analyses identified associations linking blood lower immune markerslevels of and BCL incidence. In particular, we identified growth factors, and within that family, fibroblast growth factor-2 (FGF-2 , p=7.2x10 -4 ), ) and transforming growth factor alpha (TGF-α , p=6.5x10 -5 ) and BCL incidence. Analyses stratified by histological subtypes identified inverse associations for MM subtype including FGF-2 (p=7.8x10 -7 ), TGF-α (p=4.08x10 -5 ), fractalkine (p=1.12x10 -3 ), monocyte chemotactic protein-3 (p=1.36x10 -4 ), macrophage inflammatory protein 1-alpha (p=4.6x10 -4 ), and vascular endothelial growth factor (p=4.23x10 -5 ). , and vascular endothelial growth factor (VEGF), to be consistently (and inversely) associated with MM incidence. Our results also provide d marginal support for already reported associations between chemokines and diffuse large B-Cell lymphoma (DLBCL) , and cytokines and chronic lymphocytic leukemia (CLL) . Case-only analyses showed that GM-CSF 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.