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A cohort of 25 patients with MCL at diagnosis and the first relapse after the failure of standard immunochemotherapy was analyzed using whole\u2010exome sequencing. The most frequent variants at diagnosis and at relapse comprised six genes: <jats:italic>TP53<\/jats:italic>, <jats:italic>ATM<\/jats:italic>, <jats:italic>KMT2D<\/jats:italic>, <jats:italic>CCND1<\/jats:italic>, <jats:italic>SP140<\/jats:italic>, and <jats:italic>LRP1B<\/jats:italic>. The most frequent CNVs at diagnosis and at relapse included <jats:italic>TP53<\/jats:italic> and <jats:italic>CDKN2A\/B<\/jats:italic> deletions, and <jats:italic>PIK3CA<\/jats:italic> amplifications. The mean count of mutations per patient significantly increased at relapse (<jats:italic>n<\/jats:italic>\u2009=\u200934) compared to diagnosis (<jats:italic>n<\/jats:italic>\u2009=\u200927). The most frequent newly detected variants at relapse, <jats:italic>LRP1B<\/jats:italic> gene mutations, correlated with a higher mutational burden. Variant allele frequencies of <jats:italic>TP53<\/jats:italic> variants increased from 0.35 to 0.76 at relapse. The frequency and length of predicted CNVs significantly increased at relapse with <jats:italic>CDKN2A\/B<\/jats:italic> deletions being the most frequent. Our data suggest, that the resistant MCL clones detected at relapse were already present at diagnosis and were selected by therapy. We observed enrichment of genetic aberrations of DNA damage response pathway (<jats:italic>TP53<\/jats:italic> and <jats:italic>CDKN2A\/B<\/jats:italic>), and a significant increase in MCL heterogeneity. We identified <jats:italic>LRP1B<\/jats:italic> inactivation as a new potential driver of MCL relapse.<\/jats:p>","DOI":"10.1002\/ajh.27044","type":"journal-article","created":{"date-parts":[[2023,8,22]],"date-time":"2023-08-22T10:13:20Z","timestamp":1692699200000},"page":"1627-1636","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Sequencing\u2010based analysis of clonal evolution of 25 mantle cell lymphoma patients at diagnosis and after failure of standard immunochemotherapy"],"prefix":"10.1002","volume":"98","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3828-6000","authenticated-orcid":false,"given":"J.","family":"Karolov\u00e1","sequence":"first","affiliation":[{"name":"Institute of Pathological Physiology, First Faculty of Medicine Charles University  Prague Czech Republic"},{"name":"First Department of Medicine \u2013 Hematology University General Hospital Prague and First Faculty of Medicine, Charles 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