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We searched genomic DNA from 218 patients across four continents for recurrent DNA methylation patterns and their associations with clinical and molecular features. We identified DNA methylation patterns that were not fully explained by the Epstein\u2013Barr virus status or mutation status, leading to two epitypes described here as HypoBL and HyperBL. Each is characterized by distinct genomic and clinical features including global methylation, mutation burden, aberrant somatic hypermutation, and survival 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, pending validation in external cohorts, point to a refined risk assessment for patients with Burkitt lymphoma who may experience inferior outcomes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>Burkitt lymphoma can be divided into two epigenetic subtypes (epitypes), each carrying distinct biological, transcriptomic, genomic, and clinical features. Epitype is more strongly associated with clinical and mutational features than the Epstein\u2013Barr virus status or genetic subtype, highlighting an important additional layer of Burkitt lymphoma pathogenesis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2643-3230.bcd-24-0240","type":"journal-article","created":{"date-parts":[[2025,5,8]],"date-time":"2025-05-08T11:39:08Z","timestamp":1746704348000},"page":"325-342","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["DNA Methylation Epitypes of Burkitt Lymphoma with Distinct Molecular and Clinical Features"],"prefix":"10.1158","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-9026-2715","authenticated-orcid":false,"given":"Nicole","family":"Thomas","sequence":"first","affiliation":[{"name":"1Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, 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