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The prognostic significance of the<jats:italic>IGH<\/jats:italic>translocation is controversial and its mutational profile remains unknown. Here, we present for the first time a comprehensive next\u2010generation sequencing (NGS) analysis of 46 CLL patients with<jats:italic>IGH<\/jats:italic>rearrangement (IGH<jats:italic>R<\/jats:italic>\u2010CLLs) and we demonstrate that IGH<jats:italic>R<\/jats:italic>\u2010CLLs have a distinct mutational profile with recurrent mutations in<jats:italic>NOTCH1<\/jats:italic>,<jats:italic>IGLL5<\/jats:italic>,<jats:italic>POT1<\/jats:italic>,<jats:italic>BCL2<\/jats:italic>,<jats:italic>FBXW7<\/jats:italic>,<jats:italic>ZMYM3<\/jats:italic>,<jats:italic>MGA<\/jats:italic>,<jats:italic>BRAF<\/jats:italic>and<jats:italic>HIST1H1E<\/jats:italic>genes. Interestingly,<jats:italic>BCL2<\/jats:italic>and<jats:italic>FBXW7<\/jats:italic>mutations were significantly associated with this subgroup and almost half of<jats:italic>BCL2<\/jats:italic>,<jats:italic>IGLL5<\/jats:italic>and<jats:italic>HISTH1E<\/jats:italic>mutations reported were previously identified in non\u2010Hodgkin lymphomas. Notably,<jats:italic>IGH\/BCL2<\/jats:italic>rearrangements were associated with a lower mutation frequency and carried<jats:italic>BCL2<\/jats:italic>and<jats:italic>IGLL5<\/jats:italic>mutations, while the other IGH<jats:italic>R<\/jats:italic>\u2010CLLs had mutations in genes related to poor prognosis (<jats:italic>NOTCH1<\/jats:italic>,<jats:italic>SF3B1<\/jats:italic>and<jats:italic>TP53<\/jats:italic>) and shorter time to first treatment (TFT). Moreover, IGH<jats:italic>R<\/jats:italic>\u2010CLLs patients showed a shorter TFT than CLL patients carrying 13q\u2212, normal fluorescence in situ hybridization (FISH) and +12 CLL, being this prognosis particularly poor when<jats:italic>NOTCH1<\/jats:italic>,<jats:italic>SF3B1<\/jats:italic>,<jats:italic>TP53<\/jats:italic>,<jats:italic>BIRC3<\/jats:italic>and<jats:italic>BRAF<\/jats:italic>were also mutated. The presence of these mutations not only was an independent risk factor within IGH<jats:italic>R<\/jats:italic>\u2010CLLs, but also refined the prognosis of low\u2010risk cytogenetic patients (13q\u2212\/normal FISH). Hence, our study demonstrates that IGH<jats:italic>R<\/jats:italic>\u2010CLLs have a distinct mutational profile from the majority of CLLs and highlights the relevance of incorporating NGS and the status of<jats:italic>IGH<\/jats:italic>by FISH analysis to refine the risk\u2010stratification CLL model.<\/jats:p>","DOI":"10.1002\/ijc.33235","type":"journal-article","created":{"date-parts":[[2020,7,28]],"date-time":"2020-07-28T07:21:36Z","timestamp":1595920896000},"page":"2780-2792","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Chronic lymphocytic leukemia patients with<scp><i>IGH<\/i><\/scp>translocations are characterized by a distinct genetic landscape with prognostic implications"],"prefix":"10.1002","volume":"147","author":[{"given":"Claudia","family":"P\u00e9rez\u2010Carretero","sequence":"first","affiliation":[{"name":"Universidad de Salamanca, IBSAL, Centro de Investigaci\u00f3n del C\u00e1ncer, 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