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Recent integrative, multi-omic analyses had led to identifying overlapping genetic DLBCL subtypes. We used targeted massive sequencing to analyze 84 diagnostic samples from a multicenter cohort of patients with DLBCL treated with rituximab-containing therapies and a median follow-up of 6\u00a0years. The most frequently mutated genes were <jats:italic>IGLL5<\/jats:italic> (43%), <jats:italic>KMT2D<\/jats:italic> (33.3%), <jats:italic>CREBBP<\/jats:italic> (28.6%), <jats:italic>PIM1<\/jats:italic> (26.2%), and <jats:italic>CARD11<\/jats:italic> (22.6%). Mutations in <jats:italic>CD79B<\/jats:italic> were associated with a higher risk of relapse after treatment, whereas patients with mutations in <jats:italic>CD79B<\/jats:italic>, <jats:italic>ETS1,<\/jats:italic> and <jats:italic>CD58<\/jats:italic> had a significantly shorter survival. Based on the new genetic DLBCL classifications, we tested and validated a simplified method to classify samples in five genetic subtypes analyzing the mutational status of 26 genes and <jats:italic>BCL2<\/jats:italic> and <jats:italic>BCL6<\/jats:italic> translocations. We propose a two-step genetic DLBCL classifier (2-S), integrating the most significant features from previous algorithms, to classify the samples as N1<jats:sup>2-S<\/jats:sup>, EZB<jats:sup>2-S<\/jats:sup>, MCD<jats:sup>2-S<\/jats:sup>, BN2<jats:sup>2-S<\/jats:sup>, and ST2<jats:sup>2-S<\/jats:sup> groups. We determined its sensitivity and specificity, compared with the other established algorithms, and evaluated its clinical impact. The results showed that ST2<jats:sup>2-S<\/jats:sup> is the group with the best clinical outcome and N1<jats:sup>2-S<\/jats:sup>, the more aggressive one. EZB<jats:sup>2-S<\/jats:sup> identified a subgroup with a worse prognosis among GCB-DLBLC cases.<\/jats:p>","DOI":"10.1038\/s41598-020-80376-0","type":"journal-article","created":{"date-parts":[[2021,1,21]],"date-time":"2021-01-21T11:03:39Z","timestamp":1611227019000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Proposal and validation of a method to classify genetic subtypes of diffuse large B cell lymphoma"],"prefix":"10.1038","volume":"11","author":[{"given":"Luc\u00eda","family":"Pedrosa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ismael","family":"Fern\u00e1ndez-Miranda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"P\u00e9rez-Callejo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Quero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Rodr\u00edguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paloma","family":"Mart\u00edn-Acosta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sagrario","family":"G\u00f3mez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Gonz\u00e1lez-Rinc\u00f3n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adri\u00e1n","family":"Santos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Tarin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan F.","family":"Garc\u00eda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco R.","family":"Garc\u00eda-Arroyo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Rueda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisca I.","family":"Camacho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00f3nica","family":"Garc\u00eda-Cos\u00edo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Heredero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Llanos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Mollejo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Piris-Villaespesa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9","family":"G\u00f3mez-Codina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Yanguas-Cas\u00e1s","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"S\u00e1nchez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel A.","family":"Piris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariano","family":"Provencio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margarita","family":"S\u00e1nchez-Beato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,1,21]]},"reference":[{"key":"80376_CR1","doi-asserted-by":"publisher","first-page":"3724","DOI":"10.1182\/blood-2010-05-282632","volume":"116","author":"M Sant","year":"2010","unstructured":"Sant, M. et al. 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