Abstract PR14: Mutational landscape of diffuse large B cell lymphoma in patients with genome-defined African ancestry

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. We examined differences in baseline clinical characteristics for black and white patients with DLBCL and the relationships between race 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. Global ancestry prediction identified 619 patients with >90% European ancestry, 81 patients with >90% African ancestry, and 50 patients with >90% Asian ancestry. Compared to DLBCL patients with >90% European ancestry, patients with >90% African ancestry were younger at the time of diagnosis and more commonly presented with B symptoms, abnormally elevated serum lactate dehydrogenase, extranodal disease, and advanced stage disease. All except younger age are poor prognostic factors in DLBCL. Patients with >90% African ancestry more commonly had mutations in six DLBCL driver genes compared with patients with >90% 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), KMT2C/MLL3 (11.1% vs 4.36%; P = .013), and DNMT3A (11.1% vs 4.52%; P = .016). Patients with >90% African ancestry also demonstrated worse overall survival compared with patients with >90% European ancestry (median, 4.9 years vs 8.8 years; P = .04). We further analyzed previously identified germline genetic loci associated with DLBCL susceptibility among predominantly European populations to evaluate local chromosomal ancestry in the African ancestry group. Additional comparisons of DLBCL subtype among individuals of African compared with European ancestry are being performed using the LymphGen probabilistic classification tool for genetic subtypes of DLBCL with therapeutic implications (Wright et al. Cancer Cell. 2020). The distinct patterns of clinical characteristics, somatic mutations, genetic alterations, and subtype distributions highlight important differences in the landscape of DLBCL arising in different ancestry groups. This characterization among patients with African ancestry who are diagnosed with DLBCL provides a roadmap for future studies in other malignancies for constructing multilevel models that address race and ancestry and a pathway for drug development in areas where these genomic alterations are found to be associated with worse clinical outcomes. Citation Format: Michelle J. Lee, Jean L. Koff, Michelle A.T. Hildebrandt, Jeffrey M. Switchenko, C. I. Jhaney, R. A. Harkins, Sharvil P. Patel, Sandeep S. Dave, Christopher R. Flowers. Mutational landscape of diffuse large B cell lymphoma in patients with genome-defined African ancestry [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PR14.