title: Mutations in the cohesin complex in acute myeloid leukemia: clinical and prognostic implications.
abstract: Mutations in the cohesin complex are novel, genetic lesions in acute myeloid leukemia (AML) that are not well characterized. In this study, we analyzed the frequency, clinical, and prognostic implications of mutations in STAG1, STAG2, SMC1A, SMC3, and RAD21, all members of the cohesin complex, in a cohort of 389 uniformly treated AML patients by next generation sequencing. We identified a total of 23 patients (5.9%) with somatic mutations in 1 of the cohesin genes. All gene mutations were mutually exclusive, and STAG1 (1.8%), STAG2 (1.3%), and SMC3 (1.3%) were most frequently mutated. Patients with any cohesin complex mutation had lower BAALC expression levels. We found a strong association between mutations affecting the cohesin complex and NPM1. Mutated allele frequencies were similar between NPM1 and cohesin gene mutations. Overall survival (OS), relapse-free survival (RFS), and complete remission rates (CR) were not influenced by the presence of cohesin mutations (OS: hazard ratio [HR] 0.98; 95% confidence interval [CI], 0.56-1.72 [P = .94]; RFS: HR 0.7; 95% CI, 0.36-1.38 [P = .3]; CR: mutated 83% vs wild-type 76% [P = .45]). The cohesin complex presents a novel pathway affected by recurrent mutations in AML. This study is registered at www.clinicaltrials.gov as #NCT00209833.
authors: Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany;
authors: Felicitas
authors: F
authors: Thol
authors: Robin
authors: R
authors: Bollin
authors: Marten
authors: M
authors: Gehlhaar
authors: Carolin
authors: C
authors: Walter
authors: Martin
authors: M
authors: Dugas
authors: Karl Josef
authors: KJ
authors: Suchanek
authors: Aylin
authors: A
authors: Kirchner
authors: Liu
authors: L
authors: Huang
authors: Anuhar
authors: A
authors: Chaturvedi
authors: Martin
authors: M
authors: Wichmann
authors: Lutz
authors: L
authors: Wiehlmann
authors: Rabia
authors: R
authors: Shahswar
authors: Frederik
authors: F
authors: Damm
authors: Gudrun
authors: G
authors: Göhring
authors: Brigitte
authors: B
authors: Schlegelberger
authors: Richard
authors: R
authors: Schlenk
authors: Konstanze
authors: K
authors: Döhner
authors: Hartmut
authors: H
authors: Döhner
authors: Jürgen
authors: J
authors: Krauter
authors: Arnold
authors: A
authors: Ganser
authors: Michael
authors: M
authors: Heuser
mesh_terms: D000293:Adolescent; D000328:Adult; D034961:Antigens, Nuclear / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000235:genetics*; D011508:Chondroitin Sulfate Proteoglycans / Q000235:genetics*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D020732:Cytogenetic Analysis; D004268:DNA-Binding Proteins; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000401:mortality* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000378:metabolism; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics*; D000090243:Nucleophosmin; D010750:Phosphoproteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011379:Prognosis; D012074:Remission Induction; D015996:Survival Rate; D055815:Young Adult; D000098550:Structural Maintenance of Chromosome Protein 1; D000097722:Cohesins
chemical_list: D034961:Antigens, Nuclear; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D011508:Chondroitin Sulfate Proteoglycans; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000090243:Nucleophosmin; D010750:Phosphoproteins; D000098550:Structural Maintenance of Chromosome Protein 1; C442828:BAALC protein, human; C000716967:NPM1 protein, human; C429022:RAD21 protein, human; C492318:SMC3 protein, human; C108522:STAG1 protein, human; C508565:STAG2 protein, human; D000097722:Cohesins