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DNA methylation epitypes of Burkitt lymphoma with distinct molecular and clinical features

ABSTRACT: The genetic drivers of Burkitt Lymphoma (BL) have been comprehensively explored while the role of epigenetics remains unclear. Using samples from patients across four continents, we searched for sites with consistent DNA methylation changes and associations with clinical and molecular features such as Epstein-Barr virus (EBV) status and driver mutations. We identified robust methylation patterns that were not fully explained by EBV status, implying the existence of robust epitypes: HypoBL and HyperBL. The latter had distinct genomic and clinical features including global hypermethylation, a higher mutation burden, elevated aberrant somatic hypermutation, and inferior outcomes. Methylation, gene expression and mutational differences between the epitypes support a model in which each arises from a distinct cell-of-origin. These results suggest an approach for identifying BL patients with a greater risk of treatment failure and provide a basis for the exploration of new therapeutic strategies that target the unique molecular underpinnings of each group.

ORGANISM(S): Homo sapiens

PROVIDER: GSE292690 | GEO | 2025/03/26

REPOSITORIES: GEO

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Project description:Sporadic Burkitt lymphoma (sBL) can be delineated from diffuse large B-cell lymphoma (DLBCL) by a very homogeneous mRNA expression signature. However, it remained unclear whether all three BL variants – sBL, endemic BL (eBL) and immunodeficiency-associated BL (HIV-BL) – represent a uniform biological entity despite their differences in geographical occurrence, association with immunodeficiency and/or incidence of EBV infection. To address this issue, we generated micro RNA (miRNA) profiles from 18 eBL, 31 sBL and 15 HIV-BL cases. In addition, we analyzed the miRNA expression of 86 DLBCL to determine whether miRNA profiles recapitulate the molecular differences between BL and DLBCL evidenced by mRNA profiling. A signature of 38 miRNAs enriched in MYC regulated and NF-kB pathway associated miRNAs was obtained that differentiated BL from DLBCL. The miRNA profiles of sBL and eBL displayed only 6 differentially expressed miRNAs, whereas HIV and EBV infection had no impact on the miRNA profile of BL. In conclusion, miRNA profiling confirms that BL and DLBCL represent distinct lymphoma categories and demonstrates that the three BL variants are representatives of the same biological entity with only marginal miRNA expression differences between eBL and sBL. Archival tumor specimens of 86 diffuse large B-cell lymphoma (DLBCL) and 64 Burkitt lymphoma (BL) patients were obtained. The DLBCL samples have previously been reviewed by a panel of expert hematopathologists and their clinical data were published as part of the RiCOVER-60 trial. The diagnosis of all BL cases was confirmed by histopathology review according to the criteria of the WHO classification. Based on their geographical origin, 31 BL samples were designated as sporadic BL (sBL) and 18 samples as endemic BL (eBL). Fifteen BL cases were diagnosed as immunodeficiency-associated BL (HIV-BL). Of the 18 eBL 14 cases were EBV+ (87.5%), 2 samples were EBV- (12.5%) and for 2 eBL cases the EBV status was unknown. Of the sBL samples 26 were EBV- (86.7%), 4 cases were EBV+ (13.3%) and for 1 case the EBV status was not evaluable. Among the HIV-BL 5 (33.3%) were EBV+, whereas 10 (66.7%) were EBV-.

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DNA methylation epitypes of Burkitt lymphoma with distinct molecular and clinical features

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