title: Next-generation sequencing of acute myeloid leukemia identifies the significance of TP53, U2AF1, ASXL1, and TET2 mutations.
abstract: We assessed the frequency and clinicopathologic significance of 19 genes currently identified as significantly mutated in myeloid neoplasms, RUNX1, ASXL1, TET2, CEBPA, IDH1, IDH2, DNMT3A, FLT3, NPM1, TP53, NRAS, EZH2, CBL, U2AF1, SF3B1, SRSF2, JAK2, CSF3R, and SETBP1, across 93 cases of acute myeloid leukemia (AML) using capture target enrichment and next-generation sequencing. Of these cases, 79% showed at least one nonsynonymous mutation, and cases of AML with recurrent genetic abnormalities showed a lower frequency of mutations versus AML with myelodysplasia-related changes (P<0.001). Mutational analysis further demonstrated that TP53 mutations are associated with complex karyotype AML, whereas ASXL1 and U2AF1 mutations are associated with AML with myelodysplasia-related changes. Furthermore, U2AF1 mutations were specifically associated with trilineage morphologic dysplasia. Univariate analysis demonstrated that U2AF1 and TP53 mutations are associated with absence of clinical remission, poor overall survival (OS), and poor disease-free survival (DFS; P<0.0001), whereas TET2 and ASXL1 mutations are associated with poor OS (P<0.03). In multivariate analysis, U2AF1 and TP53 mutations retained independent prognostic significance in OS and DFS, respectively. Our results demonstrate unique relationships between mutations in AML, clinicopathologic prognosis, subtype categorization, and morphologic dysplasia.
authors.affiliation: Department of Pathology, Stanford University Medical Center, Stanford, CA, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Ohgami
authors.affiliation: Department of Pathology, Stanford University Medical Center, Stanford, CA, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Pathology, Stanford University Medical Center, Stanford, CA, USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Merker
authors.affiliation: Division of Hematology, Department of Medicine, Stanford University Medical Center, Stanford, CA, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Gotlib
authors.affiliation: Department of Pathology, Stanford University Medical Center, Stanford, CA, USA.
authors.forename: Iris
authors.initials: I
authors.lastname: Schrijver
authors.affiliation: 1] Department of Pathology, Stanford University Medical Center, Stanford, CA, USA [2] Division of Hematology, Department of Medicine, Stanford University Medical Center, Stanford, CA, USA.
authors.forename: James L
authors.initials: JL
authors.lastname: Zehnder
authors.affiliation: Department of Pathology, Stanford University Medical Center, Stanford, CA, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Arber
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D002648:Child; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics; D049308:Dioxygenases; D018572:Disease-Free Survival; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D000090243:Nucleophosmin; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D012261:Ribonucleoproteins / Q000235:genetics; D000072668:Splicing Factor U2AF; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D055815:Young Adult
chemical_list: C473949:ASXL1 protein, human; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D012261:Ribonucleoproteins; D000072668:Splicing Factor U2AF; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C076753:U2AF1 protein, human; D000090243:Nucleophosmin; D049308:Dioxygenases; C541081:TET2 protein, human