title: Recurrent genetic defects on chromosome 5q in myeloid neoplasms.
abstract: BACKGROUND
  Deletion of chromosome 5q (del(5q)) is the most common karyotypic abnormality in myeloid neoplasms.
  
  
  METHODS
  To define the pathogenic molecular features associated with del(5q), next-generation sequencing was applied to 133 patients with myeloid neoplasms (MDS; N = 69, MDS/MPN; N = 5, sAML; N = 29, pAML; N = 30) with del(5q) as a sole abnormally or a part of complex karyotype and results were compared to molecular features of patients diploid for chr5.
  
  
  RESULTS
  A number of 5q genes with haploinsufficient expression and/or recurrent somatic mutations were identified; for these genes, CSNK1A1 and G3BP1 within the commonly deleted 5q region and DDX41 within a commonly retained region were most commonly affected by somatic mutations. These genes showed consistent haploinsufficiency in deleted cases; low expression/mutations of G3BP1 or DDX41 were associated with poor survival, likely due to decreased cellular function. The most common mutations on other chromosomes in patients with del(5q) included TP53, and mutations of FLT3 (ITD or TKD), NPM1 or TET2 and were mutually exclusive. Serial sequencing allowed for definition of clonal architecture and dynamics, in patients with exome sequencing allelic imbalance for informative SNPs facilitated simultaneous approximation of clonal size of del(5q) and clonal burden for somatic mutations.
  
  
  CONCLUSIONS
  Our results illuminate the spectrum of molecular defects characteristic of del(5q), their clinical impact and succession of stepwise evolution.
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.|First Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Hosono
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Hideki
authors.initials: H
authors.lastname: Makishima
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Reda
authors.initials: R
authors.lastname: Mahfouz
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Bartlomiej
authors.initials: B
authors.lastname: Przychodzen
authors.affiliation: Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.|Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Andres
authors.initials: A
authors.lastname: Jerez
authors.affiliation: Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: LaFramboise
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Chantana
authors.initials: C
authors.lastname: Polprasert
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Clemente
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Shiraishi
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Chiba
authors.affiliation: Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.|Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.affiliation: Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.|Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Sanada
authors.affiliation: Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Cui
authors.affiliation: Department of Oncology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Amit K
authors.initials: AK
authors.lastname: Verma
authors.affiliation: Division of Hematology and Hematological Malignancy, Department of Internal Medicine and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: McDevitt
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Alan F
authors.initials: AF
authors.lastname: List
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Yogen
authors.initials: Y
authors.lastname: Saunthararajah
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.|Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.|LLR Molecular Haematology Unit, Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Mikkael A
authors.initials: MA
authors.lastname: Sekeres
authors.affiliation: LLR Molecular Haematology Unit, Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Boultwood
authors.affiliation: Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.|Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.|Leukemia Program, Cleveland Clinic, Taussig Cancer Institute, Cleveland, OH, USA.
authors.forename: Jaroslaw P
authors.initials: JP
authors.lastname: Maciejewski
mesh_terms: D000748:Anemia, Macrocytic / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D002872:Chromosome Deletion; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D004171:Diploidy; D020022:Genetic Predisposition to Disease; D057895:Haploinsufficiency; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000401:mortality / Q000473:pathology; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000090243:Nucleophosmin; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016016:Proportional Hazards Models; D017422:Sequence Analysis, DNA / Q000379:methods; D013997:Time Factors
chemical_list: D014408:Biomarkers, Tumor; C000716967:NPM1 protein, human; D000090243:Nucleophosmin
keywords: G3BP1; MDS; TP53; del(5q)