Loss-of-function mutations of BCOR are an independent marker of adverse outcomes in intensively treated patients with acute myeloid leukemia

  • Simple Summary: Acute myeloid leukemia (AML) is a genetically heterogeneous disease. Clinical phenotypes of frequent mutations and their impact on patient outcome are well established. However, the role of rare mutations often remains elusive. We retrospectively analyzed 1529 newly diagnosed and intensively treated AML patients for mutations of BCOR and BCORL1. We report a distinct co-mutational pattern that suggests a role in disease progression rather than initiation, especially affecting mechanisms of DNA-methylation. Further, we found loss-of-function mutations of BCOR to be independent markers of poor outcomes in multivariable analysis. Therefore, loss-of-function mutations of BCOR need to be considered for AML management, as they may influence risk stratification and subsequent treatment allocation. Abstract: Acute myeloid leukemia (AML) is characterized by recurrent genetic events. The BCL6 corepressor (BCOR) and its homolog, the BCL6 corepressor-like 1 (BCORL1), have been reported to be rare but recurrent mutations in AML. Previously, smaller studies have reported conflicting results regarding impacts on outcomes. Here, we retrospectively analyzed a large cohort of 1529 patients with newly diagnosed and intensively treated AML. BCOR and BCORL1 mutations were found in 71 (4.6%) and 53 patients (3.5%), respectively. Frequently co-mutated genes were DNTM3A, TET2 and RUNX1. Mutated BCORL1 and loss-of-function mutations of BCOR were significantly more common in the ELN2017 intermediate-risk group. Patients harboring loss-of-function mutations of BCOR had a significantly reduced median event-free survival (HR = 1.464 (95%-Confidence Interval (CI): 1.005–2.134), p = 0.047), relapse-free survival (HR = 1.904 (95%-CI: 1.163–3.117), p = 0.01), and trend for reduced overall survival (HR = 1.495 (95%-CI: 0.990–2.258), p = 0.056) in multivariable analysis. Our study establishes a novel role for loss-of-function mutations of BCOR regarding risk stratification in AML, which may influence treatment allocation.

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Author:Jan-Niklas EckardtORCiDGND, Sebastian StasikORCiDGND, Michael Kramer, Christoph Röllig, Alwin KrämerORCiDGND, Sebastian Scholl, Andreas Hochhaus, Martina Crysandt, Tim Henrik Brümmendorf, Ralph NaumannGND, Björn SteffenGND, Volker Kunzmann, Hermann EinseleORCiDGND, Markus Schaich, Andreas BurchertORCiDGND, Andreas NeubauerORCiD, Kerstin Schäfer-Eckart, Christoph Schliemann, Stefan W. KrauseORCiDGND, Regina Herbst, Mathias Hänel, Norbert Frickhofen, Richard Noppeney, Ulrich Kaiser, Claudia BaldusORCiDGND, Martin Kaufmann, Zdenek Rácil, Uwe PlatzbeckerORCiDGND, Wolfgang E. Berdel, Jiří Mayer, Hubert ServeORCiDGND, Carsten Müller-TidowORCiDGND, Gerhard EhningerGND, Friedrich Stölzel, Frank Kroschinsky, Johannes Schetelig, Martin Bornhäuser, Christian Thiede, Jan Moritz Middeke
Parent Title (English):Cancers
Place of publication:Basel
Document Type:Article
Date of Publication (online):2021/04/26
Date of first Publication:2021/04/26
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2021/09/28
Tag:BCOR; BCORL1; acute myeloid leukemia; loss-of-function; risk stratification; survival
Issue:9, art. 2095
Page Number:15
First Page:1
Last Page:15
Open Access Funding by the Publication Fund of the TU Dresden.
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0