Racial Differences in the Molecular Genetic Biomarkers of Diffuse Large B-Cell Lymphoma

<b>Background/Objectives:</b> Diffuse large B-cell lymphoma (DLBCL) exhibits pronounced racial disparities in incidence and outcomes, yet the molecular basis remains poorly understood. Here, we examined racial differences in gene rearrangements (<i>MYC</i>, <i>BCL2</i>, <i>BCL6</i>), fusions (<i>IGH</i>::<i>MYC</i>, <i>IGH</i>::<i>BCL2</i>), and their interactions among White, Black, Asian, and Other-race groups in patients with DLBCL to uncover genetic drivers of disparities. <b>Methods:</b> We analyzed 919 DLBCL cases (2006-2023) from Johns Hopkins Hospital using fluorescence in situ hybridization to detect gene abnormalities. We used logistic regression and proportional odds models, adjusted for age and sex, to evaluate racial differences in five gene abnormalities and 10 gene-gene interaction pairs. Pearson's Chi-squared and Goodman-Kruskal's gamma tests assessed prevalence and interaction severity across racial groups. <b>Results:</b><i>MYC</i> rearrangements and the <i>MYC</i>*<i>IGH</i>::<i>MYC</i> interaction were marginally more frequent in the White group than in Black and Other groups (<i>p</i> = 0.092, <i>p</i> = 0.098, respectively). <i>IGH</i>::<i>BCL2</i> fusions were more prevalent in the Asian group than in the White group (<i>p</i> = 0.095), and the <i>BCL2</i>*<i>IGH</i>::<i>BCL2</i> interaction was significantly higher in the Asian group (<i>p</i> = 0.049) than in the White group. Although high-grade B-cell lymphoma (HGBCL) prevalence showed no significant racial differences (<i>p</i> = 0.16), the Asian group exhibited a higher proportion of aggressive HGBCL with concurrent <i>IGH</i>::<i>MYC</i> and <i>IGH</i>::<i>BCL2</i> fusions compared with the White group (<i>p</i> = 0.076). Age significantly influenced all gene abnormalities and interactions (<i>p</i> < 0.001-0.052), except for <i>MYC</i> rearrangements and specific pairs. Sex and sex-race interactions showed no significant effects. <b>Conclusions:</b> This study highlights molecular contributions to the racial differences in DLBCL disease. Further research collecting ancestry-specific biomarkers, treatment regimens, and clinical variables and outcomes is needed to advance personalized treatment strategies.