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

• Type of Material: Article
• Authors: Michelle J Lee, Emory University; Jean Koff, Emory University; Jeffrey Switchenko, Emory University; Camber Ileen Jhaney, Emory University; Andrew R Harkins, Emory University; Sharvil P Patel, Emory University; Sandeep S Dave, Duke University; Christopher Flowers, Emory University
• Language: English
• Date: 2020-05-29
• Publisher: WILEY
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2020 American Cancer Society
• Final Published Version (URL): http://dx.doi.org/10.1002/cncr.32866
• Title of Journal or Parent Work: CANCER
• Volume: 126
• Issue: 15
• Start Page: 3493
• End Page: 3503
• Grant/Funding Information: Research reported in this publication was supported by the Burroughs Wellcome Research Fund, the V Foundation, and by the National Cancer Institute of the National Institutes of Health under award number K24 CA208132. Support for this work was also provided by the Winship Research Informatics shared resource of Winship Cancer Institute of Emory University and NIH/NCI under award number P30CA138292. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
• Keywords: RACIAL-DIFFERENCES; Science & Technology; racial factors; CHEMOTHERAPY; EXPRESSION; ATM; mutation; Oncology; Life Sciences & Biomedicine; SETD2; SUBTYPE; SUSCEPTIBILITY; OUTCOMES; diffuse large B-cell lymphoma; African continental ancestry group; DISPARITIES; FEATURES

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 <.001), MGA (19.7% vs 5.33%; P <.001), SETD2 (17.3% vs 5.17%; P <.001), TET2 (12.3% vs 5.82%; P =.029), MLL3 (KMT2C) (11.1% vs 4.36%; P =.013), and DNMT3A (11.1% vs 4.52%; P =.016). Conclusions: Distinct prevalence and patterns of mutation highlight an important difference in the mutational landscapes of DLBCL arising in different ancestry groups. To the authors' knowledge, the results of the current study provide the first-ever characterization of genetic alterations among patients with African descent who are diagnosed with DLBCL.