Abstract IA29: Genome-estimated African ancestry is associated with distinct tumor mutations and poorer survival in patients with diffuse large B-cell lymphoma

Abstract

Abstract Significant differences have been observed in the incidence, age of onset, and clinical outcomes of diffuse large B-cell lymphoma (DLBCL) by race in the United States. However, it remains unclear what factors underlie these differences and whether genomic differences contribute to these disparities. In this talk Dr. Flowers will address the identified differences in baseline clinical characteristics for black and white patients with DLBCL and the relationships between race, sociodemographic factors, and outcomes. To understand the influences of genetic ancestry on tumor genomic alterations, in a recent paper (Lee et al., Cancer 2020), we estimated the genetic ancestry of 1,001 previously described patients with DLBCL (Reddy et al., Cell 2017) 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. 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). Distinct prevalence and patterns of mutation highlight an important difference in the mutational landscapes of DLBCL arising in different ancestry groups. This characterization of genetic alterations among patients with African descent who are diagnosed with DLBCL provides a roadmap for future studies in other lymphoid malignancies and a pathway for drug development in areas where these genetic alterations are found to be associated with worse clinical outcomes. Citation Format: Christopher R. Flowers. Genome-estimated African ancestry is associated with distinct tumor mutations and poorer survival in patients with diffuse large B-cell lymphoma [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr IA29.