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Subtyping Burkitt Lymphoma by DNA Methylation [EPIC]

ABSTRACT: Burkitt lymphoma (BL) is an aggressive germinal center B-cell-derived malignancy. Historically, sporadic, endemic, and immunodeficiency-associated epidemiological variants were distinguished which differ in the frequency of Epstein-Barr virus (EBV) association. Aiming at identifying subgroups based on DNA methylation patterns we here profiled 96 primary BL cases, 17 BL cell lines and 6 lymphoblastoid cell lines using Illumina BeadChip arrays. DNA methylation clustered the cases into each two subgroups according to EBV status, with each showing two underlying subgroups (EBV-positive: BL-mC1, BL-mC2 and EBV-negative: BL-mC3, BL-mC4). The subgroups BL-mC1/2 enriched for EBV-positive cases showed increased DNA methylation, epigenetic age and in part increased proliferation history compared to BL-mC3/4. CpGs hypermethylated in EBV-positive BLs were enriched for polycomb repressive complex 2 marks, while the CpGs hypomethylated in EBV-negative BLs were linked to B-cell receptor signaling. EBV-associated hypermethylation affected regulatory regions of genes frequently mutated in BL (e.g. CCND3, TP53), and impacted superenhancers, suggesting that hypermethylation may compensate for the lower mutation burden of oncogenic drivers in EBV-positive BLs. Though minor, but significant differences were also observed between EBV-positive endemic and sporadic cases (e.g. at the SOX11 and RUNX1 loci), our findings suggest that EBV status, rather than epidemiological variants, drive the DNA methylation-based subgrouping of BL.

ORGANISM(S): Homo sapiens

PROVIDER: GSE286029 | GEO | 2025/04/16

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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Subtyping Burkitt Lymphoma by DNA Methylation [EPIC]

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