Evaluation of Etiologic Heterogeneity for Risk of Diffuse Large B-Cell Lymphoma Subtype Defined by the 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 the COO in a clinic-based study of newly diagnosed DLBCL cases (N ¼ 638) and frequency-matched controls (N ¼ 2,253). Methods: The COO was determined on formalin-fixed, paraffin-embedded tumor tissue, with DLBCL classified as GCB (N ¼ 283), non-GCB (N ¼ 188), or undetermined/missing (N ¼ 167; mainly because of lack of tissue). Multivariable logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Results: We identified heterogeneity by the COO for low socioeconomic status (SES), which was only associated with non-GCB DLBCL (OR ¼ 1.88 for low vs. average SES; 95% CI, 1.08–3.27); alcohol use, which was only associated with GCB DLBCL (OR ¼ 0.48 for former drinkers; 95% CI, 0.29–0.80 and OR ¼ 0.47 for current drinkers; 95% CI, 0.32–0.71); and borderline heterogeneity for the regular use of regular/extra-strength aspirin, which was only associated with non-GCB DLBCL (OR ¼ 0.36; 95% CI, 0.16–0.85). In contrast, there was no significant heterogeneity by the COO for family history, medical history, or other lifestyle factors. Conclusions: Although requiring confirmation, most risk factors for DLBCL did not show etiologic heterogeneity by the COO, with some notable exceptions including alcohol use, SES, and perhaps regular use of regular/extra-strength aspirin showing associations. Impact: Mechanistically, these findings suggest that most of the DLBCL risk factors evaluated here influence lymphoma-genesis prior to differentiation into COO subtypes, with selected factors acting later.