title: Genetic alterations of the cohesin complex genes in myeloid malignancies.
abstract: Somatic cohesin mutations have been reported in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). To account for the morphologic and cytogenetic diversity of these neoplasms, a well-annotated cohort of 1060 patients with myeloid malignancies including MDS (n = 386), myeloproliferative neoplasms (MPNs) (n = 55), MDS/MPNs (n = 169), and AML (n = 450) were analyzed for cohesin gene mutational status, gene expression, and therapeutic and survival outcomes. Somatic cohesin defects were detected in 12% of patients with myeloid malignancies, whereas low expression of these genes was present in an additional 15% of patients. Mutations of cohesin genes were mutually exclusive and mostly resulted in predicted loss of function. Patients with low cohesin gene expression showed similar expression signatures as those with somatic cohesin mutations. Cross-sectional deep-sequencing analysis for clonal hierarchy demonstrated STAG2, SMC3, and RAD21 mutations to be ancestral in 18%, 18%, and 47% of cases, respectively, and each expanded to clonal dominance concordant with disease transformation. Cohesin mutations were significantly associated with RUNX1, Ras-family oncogenes, and BCOR and ASXL1 mutations and were most prevalent in high-risk MDS and secondary AML. Cohesin defects were associated with poor overall survival (27.2 vs 40 months; P = .023), especially in STAG2 mutant MDS patients surviving >12 months (median survival 35 vs 50 months; P = .017).
authors.affiliation: Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH;
authors.forename: Swapna
authors.initials: S
authors.lastname: Thota
authors.affiliation: Human Oncology and Pathogenesis Program and Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY; and.
authors.forename: Aaron D
authors.identifier: http://orcid.org/0000-0001-7039-0110
authors.initials: AD
authors.lastname: Viny
authors.affiliation: Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH;
authors.forename: Hideki
authors.initials: H
authors.lastname: Makishima
authors.affiliation: Human Oncology and Pathogenesis Program and Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY; and.
authors.forename: Barbara
authors.initials: B
authors.lastname: Spitzer
authors.affiliation: Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH.
authors.forename: Tomas
authors.identifier: http://orcid.org/0000-0002-9701-1851
authors.initials: T
authors.lastname: Radivoyevitch
authors.affiliation: Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH;
authors.forename: Bartlomiej
authors.initials: B
authors.lastname: Przychodzen
authors.affiliation: Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH;
authors.forename: Mikkael A
authors.initials: MA
authors.lastname: Sekeres
authors.affiliation: Human Oncology and Pathogenesis Program and Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY; and.
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.affiliation: Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH;
authors.forename: Jaroslaw P
authors.initials: JP
authors.lastname: Maciejewski
mesh_terms: D000368:Aged; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism; D003430:Cross-Sectional Studies; D018572:Disease-Free Survival; D005260:Female; D052138:Genes, Neoplasm; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D008297:Male; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D000097722:Cohesins
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D050676:Core Binding Factor Alpha 2 Subunit; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D000097722:Cohesins; C473949:ASXL1 protein, human; C411984:BCOR protein, human; C493728:RUNX1 protein, human