Genome-defined African ancestry is associated with distinct mutations and worse survival in patients with diffuse large B-cell lymphoma

Abstract

Background: Significant racial differences have been observed in the incidence and clinical outcomes of diffuse large B-cell lymphoma (DLBCL) in the United States, but to the authors' knowledge it remains unclear whether genomic differences contribute to these disparities. METHODS: To understand the influences of genetic ancestry on tumor genomic alterations, the authors estimated the genetic ancestry of 1001 previously described patients with DLBCL using unsupervised model-based Admixture global ancestry analysis applied to exome sequencing data and examined the mutational profile of 150 DLBCL driver genes in tumors obtained from this cohort. Results: Global ancestry prediction identified 619 patients with >90% European ancestry, 81 patients with >90% African ancestry, and 50 patients with >90% Asian ancestry. Compared with patients with DLBCL with European ancestry, patients with African ancestry were aged >10 years younger at the time of diagnosis and were more likely to present with B symptoms, elevated serum lactate dehydrogenase, extranodal disease, and advanced stage disease. Patients with African ancestry demonstrated worse overall survival compared with patients with European ancestry (median, 4.9 years vs 8.8 years; P =.04). Recurrent mutations of MLL2 (KMT2D), HIST1H1E, MYD88, BCL2, and PIM1 were found across all ancestry groups, suggesting shared mechanisms underlying tumor biology. The authors also identified 6 DLBCL driver genes that were more commonly mutated in patients with African ancestry compared with patients with European ancestry: ATM (21.0% vs 7.75%; P