title: Genetic and epigenetic characterization of hypodiploid acute lymphoblastic leukemia.
abstract: OBJECTIVE
  To investigate the genetic and epigenetic landscape of hypodiploid (<45 chromosomes) acute lymphoblastic leukemia (ALL).
  
  
  METHODS
  Single nucleotide polymorphism array, whole exome sequencing, RNA sequencing, and methylation array analyses were performed on eleven hypodiploid ALL cases.
  
  
  RESULTS
  In line with previous studies, mutations in IKZF3 and FLT3 were detected in near-haploid (25-30 chromosomes) cases. Low hypodiploidy (31-39 chromosomes) was associated with somatic TP53 mutations. Notably, mutations of this gene were also found in 3/3 high hypodiploid (40-44 chromosomes) cases, suggesting that the mutational patterns are similar in low hypodiploid and high hypodiploid ALL. The high hypodiploid ALLs frequently displayed substantial cell-to-cell variability in chromosomal content, indicative of chromosomal instability; a rare phenomenon in ALL. Gene expression analysis showed that genes on heterodisomic chromosomes were more highly expressed in hypodiploid cases. Cases clustered according to hypodiploid subtype in the unsupervised methylation analyses, but there was no association between chromosomal copy number and methylation levels. A comparison between samples obtained at diagnosis and relapse showed that the relapse did not arise from the major diagnostic clone in 3/4 cases.
  
  
  CONCLUSIONS
  Taken together, our data support the conclusion that near-haploid and low hypodiploid ALL are different with regard to mutational profiles and also suggest that ALL cases with high hypodiploidy may harbor chromosomal instability.
authors.affiliation: Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Setareh
authors.initials: S
authors.lastname: Safavi
authors.affiliation: Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden.|Department of Clinical Genetics, University and Regional Laboratories, Region Skåne, Lund, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Olsson
authors.affiliation: Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Andrea
authors.initials: A
authors.lastname: Biloglav
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Veerla
authors.affiliation: Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Molly
authors.initials: M
authors.lastname: Blendberg
authors.affiliation: Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Johnbosco
authors.initials: J
authors.lastname: Tayebwa
authors.affiliation: Department of Pediatrics, Linköping University Hospital, Linköping, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Behrendtz
authors.affiliation: Department of Pediatrics, Skåne University Hospital, Lund University, Lund, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Castor
authors.affiliation: Division of Hematology, Skåne University Hospital, Lund University, Lund, Sweden.
authors.forename: Markus
authors.initials: M
authors.lastname: Hansson
authors.affiliation: Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden.|Department of Clinical Genetics, University and Regional Laboratories, Region Skåne, Lund, Sweden.
authors.forename: Bertil
authors.initials: B
authors.lastname: Johansson
authors.affiliation: Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Kajsa
authors.initials: K
authors.lastname: Paulsson
mesh_terms: D059786:Abnormal Karyotype; D000293:Adolescent; D000328:Adult; D000368:Aged; D000782:Aneuploidy; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059467:Transcriptome / Q000235:genetics*
keywords: acute lymphoblastic leukemia; chromosomal instability; hypodiploidy; next generation sequencing