Evaluation of Etiologic Heterogeneity for Risk of Diffuse Large B-Cell Lymphoma Subtype Defined by Cell-of-Origin.

Background: Diffuse large B-cell lymphoma (DLBCL) is clinically heterogeneous, and gene expression profiling has identified at least two biologically distinct DLBCL subtypes defined by their cell-of-origin (COO): germinal center B-cell (GCB) and activate B-cell (ABC) or non-GCB. We evaluated a variety of putative DLBCL risk factors for etiologic heterogeneity by COO in a clinic-based study of newly diagnosed DLBCL cases (N=638) and frequency-matched controls (N=2253).

Methods: COO was determined on formalin-fixed, paraffin-embedded tumor tissue, with DLBCL classified as GCB (N=283), non-GCB (N=188), or undetermined/missing (N=167; mainly due to lack of tissue). Multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs).

Results: We identified heterogeneity by COO for low socioeconomic status (SES), which was only associated with non-GCB DLBCL (OR=1.88 for low vs average SES, 95%CI 1.08-3.27); alcohol use, which was only associated with GCB DLBCL (OR=0.48 for former drinkers, 95%CI 0.29-0.80; OR=0.47 for current drinkers, 95%CI 0.32-0.71); and borderline heterogeneity for regular use of regular/extra-strength aspirin, which was only associated with non-GCB DLBCL (OR=0.36, 95%CI 0.16-0.85). In contrast, there was no significant heterogeneity by COO for family history, medical history, or other lifestyle factors.

Conclusions: While requiring confirmation, most risk factors for DLBCL did not show etiologic heterogeneity by COO, with some notable exceptions including alcohol use, SES, and perhaps regular use of regular/extra-strength aspirin.

Impact: Mechanistically, these findings suggest that most of the DLBCL risk factors evaluated here influence lymphomagenesis prior to differentiation into COO subtypes, with selected factors acting later.