{"doi":"10.3390/cancers17182994","title":"The EBV-Positive Tumor Methylome Is Distinct from EBV-Negative in Diffuse Large B-Cell Lymphoma","abstract":"Backgrounds: Epstein–Barr virus (EBV) is implicated in the pathogenesis of different B-cell lymphomas and lymphoproliferative disorders, including diffuse large B-cell lymphoma (DLBCL) arising in immunodeficiency settings. Despite its clinical significance, the mechanisms of EBV-mediated lymphomagenesis across different disease subtypes remain poorly understood. Global DNA methylation profiling can provide insight into tumor heterogeneity and disease mechanisms. Methods: To further characterize the underlying biology of EBV(+) DLBCL, we performed a global methylome analysis of a cohort of EBV(+)/(−) DLBCL. Illumina MethylationEPIC array data were generated from a curated set of DLBCL tissue samples (n = 43) from a rural patient population with defined EBV status and immunodeficiency background. Differential methylation analyses were conducted using linear mixed models to identify significant methylation changes associated with EBV status. Results: Principle component analysis (PCA) and probe-level comparisons revealed a distinct, globally hypermethylated DNA methylome in EBV(+) DLBCL compared to EBV(−) cases, and an overall hypomethylated profile in all DLBCL relative to control tissues. We identified a total of 117,334 differentially methylated probes mapping to 1557 cancer-associated genes in EBV(+) versus EBV(−) DLBCL, and 330,872 probes mapping to 4230 cancer-associated genes in all DLBCL versus controls. Pathway enrichment analysis highlighted distinct biological processes in EBV(+) DLBCL, including P53 feedback loops (hypermethylated genes) and MAPK signaling (hypomethylated genes). Conclusions: These findings demonstrate that EBV(+) DLBCL is epigenetically distinct from EBV(−) disease, with alterations that may contribute to clinical heterogeneity and potentially serve as biomarkers for disease classification and therapeutic targeting.","journal":"Cancers","year":2025,"id":554144,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9512,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1451031,"name":"Ramiro Barrantes-Reynolds","orcid":"0000-0002-3653-0922","position":1,"is_corresponding":false},{"id":776659,"name":"Karine Sahakyan","orcid":null,"position":2,"is_corresponding":false},{"id":281459,"name":"Yuri Fedoriw","orcid":"0000-0002-2135-2908","position":3,"is_corresponding":false},{"id":75998,"name":"Seth Frietze","orcid":"0000-0003-4058-3661","position":4,"is_corresponding":false},{"id":1451030,"name":"Ashley K. Volaric","orcid":"0000-0001-9585-812X","position":0,"is_corresponding":true}],"reference_count":75,"raw_metadata":null,"created_at":"2026-07-19T02:54:45.872391Z","pmid":"41008837","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}