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We discovered a unique copy\u2010neutral loss of heterozygosity (CN\u2010LOH) landscape of PMBL which distinguishes this tumor from other B\u2010cell malignancies, including the biologically related diffuse large B\u2010cell lymphoma. Using single nucleotide polymorphism array analysis we identified large\u2010scale CN\u2010LOH lesions in 91% (30\/33) of diagnostic PMBLs and both investigated PMBL\u2010derived cell lines. Altogether, the cohort showed 157 extra\u2010large (25.3\u2013248.4\u00a0Mb) CN\u2010LOH lesions affecting up to 14 chromosomes per case (mean of 4.4) and resulting in a reduction of heterozygosity an average of 9.9% (range 1.3\u201351%) of the genome. Predominant involvement of terminal chromosomal segments suggests the implication of B\u2010cell specific crossover events in the pathogenesis of PMBL. Notably, CN\u2010LOH stretches non\u2010randomly clustered on 6p (60%), 15 (37.2%), and 17q (40%), and frequently co\u2010occurred with homozygous mutations in the <jats:italic>MHC I<\/jats:italic> (6p21), <jats:italic>B2M<\/jats:italic> (15q15), and <jats:italic>GNA13<\/jats:italic> (17q23) genes, respectively, as shown by preliminary whole\u2010exome\/genome sequencing data. Altogether, our findings implicate CN\u2010LOH as a novel and distinct mutational process contributing to the molecular pathogenesis of PMBL. The aberration acting as \u201csecond hit\u201d in the Knudson hypothesis, ranks as the major mechanism converting to homozygosity the PMBL\u2010related driver genes. Screening of the cohort of 199 B cell leukemia\/lymphoma whole\u2010genomes revealed significant differences in the CN\u2010LOH landscape of PMBL and other B\u2010cell malignancies, including the biologically related diffuse large B\u2010cell lymphoma.<\/jats:p>","DOI":"10.1002\/gcc.23069","type":"journal-article","created":{"date-parts":[[2022,5,25]],"date-time":"2022-05-25T12:21:41Z","timestamp":1653481301000},"page":"603-615","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Primary mediastinal large B\u2010cell lymphoma is characterized by large\u2010scale copy\u2010neutral loss of heterozygosity"],"prefix":"10.1002","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4051-4295","authenticated-orcid":false,"given":"Stefania","family":"Tuveri","sequence":"first","affiliation":[{"name":"Center for Human Genetics, KU Leuven  Leuven 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