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M.M. Epstein et al.
interest, we observed the strongest positive associations of sIL-2Rα with T-NHL risk within ten years of blood draw, a novel observation that requires confirmation in other populations.
We observed significant positive associations between CXCL13 and risk of all NHL, B-NHL, and FL, as well as borderline associations with DLBCL and other B-NHL, more than ten years after blood draw, suggesting an early role for an immune environment characterized by B-cell stimulation and aberrant B-cell trafficking. Consistent with this interpretation, a recent, large-scale genome-wide association study of FL identified CXCR5, which is the receptor for CXCL13, as a potential FL susceptibility locus.43 Further, genetic variation in CXCR5 and CXCL13 was associated with serum CXCL13 levels in a study of AIDS-NHL, and elevated serum CXCL13 levels were observed in AIDS-NHL cases more than three years prior to diagnosis.2 In contrast, elevated sCD30 levels were more strongly associated with increased risk of all NHL, B- NHL and FL within ten years of blood draw, with a partic- ularly strong association with FL within five years of blood draw. These findings suggest sCD30 may be captur- ing a more proximal pre-diagnosis increase in immune activation.
When assessed with multivariable PLR models rather than the main unconditional logistic regression analysis, the associations between immune markers and NHL end points did not change substantially, whether for aggregat- ed end points or the individual B-NHL end points. The minor discrepancies suggested somewhat improved preci- sion in the PLR models, which yielded slightly narrower confidence intervals and slightly stronger P-values for het- erogeneity by follow-up period for a few of the compar- isons. None of the discrepant findings would suggest a dif- ferent interpretation of the time- or subtype-specific model findings, however, and thus we retained the uncon- ditional logistic regression models as our primary analysis for methodological consistency across the full series of analyses we conducted.
In the analyses with restricted cubic splines, we observed evidence of significant non-linearity for associa- tions of CXCL13 and BAFF with aggregated NHL end points. Of note, those end points comprise small numbers of diverse histological subtypes of NHL which may have different etiologies. Thus, we believe that the observed non-linear associations more likely reflect sampling vari- ability and/or an artifact of potentially heterogeneous sub- type-specific associations for the subtypes in the end point groups than a true biological effect.
Together, our findings add new insight to previous pub- lications on both AIDS-NHL and HIV-unrelated NHL risk,
collectively suggesting that higher levels of immune acti- vation, and in particular heightened B-cell stimulation, may affect B-cell lymphomagenesis. Interestingly, several markers of immune activation appear to be elevated many years prior to NHL diagnosis and thus could help identify populations at higher risk for developing NHL. It is impor- tant to note that some reported associations between immune markers and all NHL risk were not replicated in analyses of individual histological subtypes; this may be due in part to subtype-specific sample sizes that limited statistical power. Significant associations between immune markers and risk of all NHL may reflect com- monalities in subtype etiologies; however, these findings may also conceal a more specific association with one or more of the less common subtypes, as illustrated by the present findings for BAFF and CLL/SLL.
This analysis of immune markers measured from prospectively collected blood specimens from two large US cohorts with lengthy follow up identified several sta- tistically significant associations with the risk of develop- ing NHL, including associations that remained statistically significant for blood samples collected five or more years prior to diagnosis.
Although our main results were fairly consistent across analytical approaches, slight variations in markers chosen by a priori and secondary analyses emphasize the impor- tance of utilizing diverse panels of immune markers in future studies seeking to characterize conditions con- ducive to NHL development. Furthermore, our findings suggest that even though an activated immune milieu may contribute to the development of multiple types of NHL, there is evidence of subtle differences in the pathogenesis of individual NHL subtypes, some of which had not been previously reported. Larger pooled studies will be impor- tant to more accurately identify homogeneous and hetero- geneous biomarkers of risk or early disease by NHL sub- type and to elucidate which are more indicative of earlier or later pathogenic changes to the immune environment.
Acknowledgments
The authors would like to thank the participants in the Nurses’ Health Study and Health Professionals Follow-up Study for their ongoing participation in the cohort studies. We thank Laura Burns for assistance with manuscript preparation, and wish to recognize the technical contributions of the Dana Farber/Harvard Cancer Center Specialized Histopathology Core Laboratory. We thank the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, and WY. The authors assume full responsibility for analyses and interpretation of these data.
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