Prediagnostic Serum Levels of Cytokines and Other Immune Markers and Risk of Non-Hodgkin Lymphoma

Abstract

While severe immune dysregulation is an established risk factor for non-Hodgkin lymphoma (NHL), it is unclear whether subclinical immune system function influences lymphomagenesis. To address this question, we conducted a nested case-control study within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial to investigate whether circulating levels of cytokines and other immune markers are associated with future risk of NHL. Selected cytokines [interleukin (IL)-4, IL-6, IL-10, tumor necrosis factor (TNF)-α] and other immune markers [soluble TNF receptor 1 (sTNF-R1), sTNF-R2, C-reactive protein (CRP), sCD27] were measured in prediagnostic serum specimens from 297 incident NHL cases and 297 individually matched controls. Odds ratios (OR) and 95% confidence intervals (CI) relating quartiles of analyte concentration to NHL risk were calculated using conditional logistic regression. Statistically significant associations with increased NHL risk were observed for elevated serum levels of sTNF-R1 (quartile 4 vs. quartile 1: OR 1.7, 95% CI 1.1–2.8; Ptrend=0.02) and sCD27 (OR 5.3, 95% CI 2.9–9.4; Ptrend<0.0001). These associations remained in analyses of cases diagnosed 6+ years following blood collection (sTNF-R1: OR 2.1, 95% CI 1.0–4.0, Ptrend=0.01; sCD27: OR 4.1, 95% CI 1.9–8.5, Ptrend=0.0001). Elevated levels of IL-10, TNF-α and sTNF-R2 were also significantly associated with increased risk of NHL overall; however, these associations weakened with increasing time from blood collection to case diagnosis, and were null for cases diagnosed 6+ years post-collection. Our findings for sTNF-R1 and sCD27, possible markers for inflammatory and B-cell stimulatory states respectively, support a role for subclinical inflammation and chronic B-cell stimulation in lymphomagenesis.

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

“…No direct evidence from our analyses provided support for the previously reported associations between TNF,9 IL138 and IL109, 10, 14 and BCL; TNF‐α,11 IL614 and IL109, 14 and FL; TNF‐α,11 IL5 and IL109 and DLBCL and TGF‐α11 and TNF9 and CLL. However, the direction of most of the previously reported associations is consistent with our findings.…”

“…As previously reported in a study involving 491 B‐NHL cases and 491 controls,9 we also find a positive correlation between levels of TNF‐α, IL10 and the incidence of all BCL, FL and DLBCL. The associations reported by Purdue et al 10, 11. and Conroy et al 14.…”

“…These studies have suggested an increased risk of BCL and or its subtypes with increased blood levels of soluble CD (sCD)23,3 sCD27,3, 4, 5 sCD30,3, 4, 5, 6, 7 soluble interleukin (sIL)‐2R,8 tumor necrosis factor (TNF),9 sTNF‐R1, 10 sTNF‐R2,10, 11 BCA‐1,5, 12 TNF‐α,10, 12 soluble vascular endothelial growth factor receptor (sVEGFR)2,11 sIL‐6R13 and IL10,9, 10, 14 while IL138 was negatively associated with the risk of BCL. Most of these studies investigated the associations looking at proteins separately.…”

Magnesium and lymphoma: opportunities in translation

“…Magnesium deficiency upregulates proinflammatory cytokines and increases oxidative stress, which contribute to the development of NHL. [14][15][16] It activates the redox-sensitive transcription factor nuclear factor kappa-B (NF-kB), whose constitutive activation is being recognized as critical in the pathogenesis of lymphoma and in the progression of EBV-induced malignancy. 17,18 NF-kB mediates various effects of viral infection that contribute to carcinogenesis such as antiapoptosis and stimulation of cellular proliferation.…”

A review of the role of lymphoma markers and occupational and environmental exposures

“…A recent case-control study, nested within the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial with a median length of 5 years follow-up from blood collection to case diagnosis, conducted by Purdue et al (2011) showed that elevated sTNF-R1 and sCD27 levels were associated with higher risk of developing NHL. These associations remained significant in analyses of cases diagnosed longer than 6 years following blood collection.…”