Genomic complexity is associated with epigenetic regulator mutations and poor prognosis in diffuse large B-cell lymphoma.

TitleGenomic complexity is associated with epigenetic regulator mutations and poor prognosis in diffuse large B-cell lymphoma.
Publication TypeJournal Article
Year of Publication2021
AuthorsYou H, Xu-Monette ZY, Wei L, Nunns H, Nagy ML, Bhagat G, Fang X, Zhu F, Visco C, Tzankov A, Dybkaer K, Chiu A, Tam W, Zu Y, Hsi ED, Hagemeister FB, Huh J, Ponzoni M, Ferreri AJM, Møller MB, Parsons BM, J van Krieken H, Piris MA, Winter JN, Li Y, Au Q, Xu B, Albitar M, Young KH
Date Published2021
KeywordsEpigenesis, Genetic, Genomics, Humans, Lymphoma, Large B-Cell, Diffuse, Mutation, Prognosis

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma with high mutation burdens but a low response rate to immune checkpoint inhibitors. In this study, we performed targeted next-generation sequencing and fluorescent multiplex immunohistochemistry, and investigated the clinical significance and immunological effect of mutation numbers in 424 DLBCL patients treated with standard immunochemotherapy. We found that and nonsynonymous mutations (MUT) were significantly associated with increased nonsynonymous mutation numbers, and that high mutation numbers (MUT) were associated with significantly poorer clinical outcome in germinal center B-cell-like DLBCL with wild-type . To understand the underlying mechanisms, we identified a gene-expression profiling signature and the association of MUT with decreased T cells in DLBCL patients with wild-type . On the other hand, in overall cohort, MUT was associated with lower PD-1 expression in T cells and PD-L1 expression in macrophages, suggesting a positive role of MUT in immune responses. Analysis in a whole-exome sequencing dataset of 304 patients deposited by Chapuy et al. validated the correlation of MUT- with genomic complexity and the significantly poorer survival associated with higher numbers of genomic single nucleotide variants in activated B-cell-like DLBCL with wild-type . Together, these results suggest that KMT2D inactivation or epigenetic dysregulation has a role in driving DLBCL genomic instability, and that genomic complexity has adverse impact on clinical outcome in DLBCL patients with wild-type treated with standard immunochemotherapy. The oncoimmune data in this study have important implications for biomarker and therapeutic studies in DLBCL.

Alternate JournalOncoimmunology
PubMed ID34350060
PubMed Central IDPMC8293967
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