title: RUNX1 mutations in acute myeloid leukemia are associated with distinct clinico-pathologic and genetic features.
abstract: We evaluated the frequency, genetic architecture, clinico-pathologic features and prognostic impact of RUNX1 mutations in 2439 adult patients with newly-diagnosed acute myeloid leukemia (AML). RUNX1 mutations were found in 245 of 2439 (10%) patients; were almost mutually exclusive of AML with recurrent genetic abnormalities; and they co-occurred with a complex pattern of gene mutations, frequently involving mutations in epigenetic modifiers (ASXL1, IDH2, KMT2A, EZH2), components of the spliceosome complex (SRSF2, SF3B1) and STAG2, PHF6, BCOR. RUNX1 mutations were associated with older age (16-59 years: 8.5%; ⩾60 years: 15.1%), male gender, more immature morphology and secondary AML evolving from myelodysplastic syndrome. In univariable analyses, RUNX1 mutations were associated with inferior event-free (EFS, P<0.0001), relapse-free (RFS, P=0.0007) and overall survival (OS, P<0.0001) in all patients, remaining significant when age was considered. In multivariable analysis, RUNX1 mutations predicted for inferior EFS (P=0.01). The effect of co-mutation varied by partner gene, where patients with the secondary genotypes RUNX1mut/ASXL1mut(OS, P=0.004), RUNX1mut/SRSF2mut(OS, P=0.007) and RUNX1mut/PHF6mut(OS, P=0.03) did significantly worse, whereas patients with the genotype RUNX1mut/IDH2mut(OS, P=0.04) had a better outcome. In conclusion, RUNX1-mutated AML is associated with a complex mutation cluster and is correlated with distinct clinico-pathologic features and inferior prognosis.
authors.affiliation: Klinik für Innere Medizin III, Universitätsklinikum Ulm, Ulm, Germany.
authors.forename: V I
authors.initials: VI
authors.lastname: Gaidzik
authors.affiliation: Klinik für Innere Medizin III, Universitätsklinikum Ulm, Ulm, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Teleanu
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Cambridge, UK.
authors.forename: E
authors.initials: E
authors.lastname: Papaemmanuil
authors.affiliation: Klinik für Innere Medizin III, Universitätsklinikum Ulm, Ulm, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Weber
authors.affiliation: Klinik für Innere Medizin III, Universitätsklinikum Ulm, Ulm, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Paschka
authors.affiliation: Klinik für Innere Medizin III, Universitätsklinikum Ulm, Ulm, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Hahn
authors.affiliation: Klinik für Innere Medizin III, Universitätsklinikum Ulm, Ulm, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Wallrabenstein
authors.affiliation: Klinik für Innere Medizin III, Universitätsklinikum Ulm, Ulm, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Kolbinger
authors.affiliation: Klinik für Hämatologie und Onkologie, Klinikum Oldenburg, Oldenburg, Germany.
authors.forename: C H
authors.initials: CH
authors.lastname: Köhne
authors.affiliation: Klinik für Innere Medizin II, Universitätsklinikum Schleswig-Holstein Campus Kiel, Kiel, Germany.
authors.forename: H A
authors.initials: HA
authors.lastname: Horst
authors.affiliation: Medizinische Klinik und Poliklinik III, Universitätsklinikum Bonn, Bonn, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Brossart
authors.affiliation: Klinik für Innere Medizin I, Universitätskliniken des Saarlandes, Homburg, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Held
authors.affiliation: Klinik für Hämatologie, Onkologie und Klinische Onkologie, Universitätsklinikum Düsseldorf, Düsseldorf, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Kündgen
authors.affiliation: Medizinische Klinik III, Städtisches Klinikum Karlsruhe gGmbH, Karlsruhe, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Ringhoffer
authors.affiliation: III. Medizinische Klinik, Klinikum Rechts der Isar, Technische Universität München, München, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Götze
authors.affiliation: Medizinische Klinik IV, Universitätsklinikum Gießen, Gießen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Rummel
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Cambridge, UK.
authors.forename: M
authors.initials: M
authors.lastname: Gerstung
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Cambridge, UK.
authors.forename: P
authors.initials: P
authors.lastname: Campbell
authors.affiliation: Medical Systems Biology, Universität Ulm, Ulm, Germany.
authors.forename: J M
authors.initials: JM
authors.lastname: Kraus
authors.affiliation: Medical Systems Biology, Universität Ulm, Ulm, Germany.
authors.forename: H A
authors.initials: HA
authors.lastname: Kestler
authors.affiliation: Klinik für Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation, Medizinische Hochschule Hannover, Hannover, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Thol
authors.affiliation: Klinik für Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation, Medizinische Hochschule Hannover, Hannover, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Heuser
authors.affiliation: Klinik für Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation, Medizinische Hochschule Hannover, Hannover, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Schlegelberger
authors.affiliation: Klinik für Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation, Medizinische Hochschule Hannover, Hannover, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Ganser
authors.affiliation: Klinik für Innere Medizin III, Universitätsklinikum Ulm, Ulm, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Bullinger
authors.affiliation: Klinik für Innere Medizin III, Universitätsklinikum Ulm, Ulm, Germany.
authors.forename: R F
authors.initials: RF
authors.lastname: Schlenk
authors.affiliation: Klinik für Innere Medizin III, Universitätsklinikum Ulm, Ulm, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Döhner
authors.affiliation: Klinik für Innere Medizin III, Universitätsklinikum Ulm, Ulm, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Döhner
mesh_terms: D000293:Adolescent; D000367:Age Factors; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D018572:Disease-Free Survival; D057890:Epigenomics; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D012737:Sex Factors; D017381:Spliceosomes / Q000235:genetics; D015996:Survival Rate; D055815:Young Adult
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; C493728:RUNX1 protein, human