Prediagnostic serum sCD27 and sCD30 in serial samples and risks of non‐Hodgkin lymphoma subtypes

Abstract

Elevated prediagnostic serum levels of the immune activation markers sCD27 and sCD30 have been associated with non-Hodgkin lymphoma (NHL). However, the use of a single sample per participant in these studies has limited etiologic inferences. We report findings, overall and by NHL subtype, from a case-control analysis (422 cases, 434 controls) within the Janus Serum Bank with two samples per subject collected on average 5 years apart. Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) was associated with elevated sCD27 in the later, but not earlier, prediagnostic sample (odds ratio [OR] 4.2, 95% confidence interval [CI] 1.5-11.6 and 1.7, 0.7-4.7 per log increase, respectively) in analyses adjusting for both analytes, while follicular lymphoma (FL) was associated with elevated sCD30 in both the later and earlier samples (OR 2.9, 95% CI 1.4-4.4 and 2.3, 1.2-4.4, respectively). CLL/SLL cases were significantly more likely than controls to have higher sCD27 in the later vs. earlier sample (OR 1.4, 95% CI 1.1-1.9 per standard deviation increase); no such difference in sCD30 was apparent for FL. In a joint analysis, NHL cases were more likely than controls to have below-median sCD27 in the earlier sample and above-median sCD27 in the later sample (OR 1.5, 95% CI 1.0-2.3). For sCD30, the association between sCD30 and FL was confined to subjects with above-median analyte levels in both samples (OR 2.5, 95% CI 1.1-5.9). Our findings are compatible with elevated sCD27 representing a disease-induced effect and sCD30 representing a marker of increased FL susceptibility.Additional Supporting Information may be found in the online version of this article.

Circulating immune markers and risks of non‐Hodgkin lymphoma subtypes: A pooled analysis

“…In an attempt to include all published nested case-control studies investigating NHL and prediagnostic concentrations of these immune markers that were conducted in general population cohorts (eg, excluding cohorts of subjects with HIV/AIDS), we sought to also include data from studies conducted within the Janus Serum Bank, the Northern Sweden Health study and the European Prospective Investigation into Cancer and Nutrition study. 23,24,27 However, this could not be accomplished due to data sharing restrictions related to the European Union General Data Protection Regulation Policy. 30 It is notable that many of the studies included in our pooled analysis used different assays, and/or the same assays at different points in calendar time, to measure the same immune markers (Table S1).…”

“…The markers most consistently associated with NHL include soluble CD27 (sCD27) and sCD30, which are cleaved fragments of the lymphocyte transmembrane proteins CD27 and CD30 measured as markers of immune activation, and chemokine ligand-13 (CXCL13), a B cell chemoattractant to secondary lymphoid tissue. [15][16][17][18][19][20][21][22][23][24][25][26][27] Most studies have reported that elevated levels of these three immune markers are associated with increased subsequent risk of NHL, although it is unclear to what extent these associations vary by lymphoma subtype or reflect early disease-induced effects, as has been suggested by some longitudinal studies. 24,25,28 The precise time frame that would reflect disease-induced rather than etiologic effects is not known for most subtypes; the known differences in the aggressiveness of pathogenesis between, for example, the aggressive DLBCL subtype and the more indolent subtypes like CLL/SLL, FL or MZL suggest subtype-specific variability in the preclinical stages.…”

“…[15][16][17][18][19][20][21][22][23][24][25][26][27] Most studies have reported that elevated levels of these three immune markers are associated with increased subsequent risk of NHL, although it is unclear to what extent these associations vary by lymphoma subtype or reflect early disease-induced effects, as has been suggested by some longitudinal studies. 24,25,28 The precise time frame that would reflect disease-induced rather than etiologic effects is not known for most subtypes; the known differences in the aggressiveness of pathogenesis between, for example, the aggressive DLBCL subtype and the more indolent subtypes like CLL/SLL, FL or MZL suggest subtype-specific variability in the preclinical stages. 29 Several studies have individually explored associations with common subtypes, although these investigations have typically been limited by sample size.…”

“…29 Several studies have individually explored associations with common subtypes, although these investigations have typically been limited by sample size. 15,[17][18][19]21,[24][25][26][27] Rarer subtypes such as MZL, TCL and MCL have been studied infrequently, with often uninformative findings. 24,26,27 To clarify the relationship between circulating levels of sCD27, sCD30, CXCL13 and risk of individual NHL subtypes, both overall and across varying periods of follow-up, we conducted a pooled analysis across eight nested case-control studies that measured at least one of these three markers.…”

Pre‐diagnostic levels of sVEGFR2, sTNFR2, sIL‐2Rα and sIL‐6R are associated with glioma risk: A nested case–control study of repeated samples

“…Interestingly, haematological malignancies and glioma have some common aetiological pathways, such as exposure to ionising radiation and an inverse relationship with asthma and allergies 7 . In lymphoma studies, analysis of several relevant proteins, including sCD23, sCD27, sCD30 and CXCL13, in pre‐diagnostic plasma samples have shown a significant difference between cases and controls even several years before diagnosis 8,9 . However, little is known about how the subclinical immunologic perturbations influence glioma risk.…”