title: Deep sequencing and SNP array analyses of pediatric T-cell acute lymphoblastic leukemia reveal NOTCH1 mutations in minor subclones and a high incidence of uniparental isodisomies affecting CDKN2A.
abstract: BACKGROUND
  Pediatric T-cell acute lymphoblastic leukemia (T-ALL) is a genetically heterogeneous disease that arises in a multistep fashion through acquisition of several genetic aberrations, subsequently giving rise to a malignant, clonal expansion of T-lymphoblasts. The aim of the present study was to identify additional as well as cooperative genetic events in T-ALL.
  
  
  METHODS
  A population-based pediatric T-ALL series comprising 47 cases was investigated by SNP array and deep sequencing analyses of 75 genes, in order to ascertain pathogenetically pertinent aberrations and to identify cooperative events.
  
  
  RESULTS
  The majority (92%) of cases harbored copy number aberrations/uniparental isodisomies (UPIDs), with a median of three changes (range 0-11) per case. The genes recurrently deleted comprised CDKN2A, CDKN2B, LEF1, PTEN, RBI, and STIL. No case had a whole chromosome UPID; in fact, literature data show that this is a rare phenomenon in T-ALL. However, segmental UPIDs (sUPIDs) were seen in 42% of our cases, with most being sUPID9p that always were associated with homozygous CDKN2A deletions, with a heterozygous deletion occurring prior to the sUPID9p in all instances. Among the 75 genes sequenced, 14 (19%) were mutated in 28 (72%) of 39 analyzed cases. The genes targeted are involved in signaling transduction, epigenetic regulation, and transcription. In some cases, NOTCH1 mutations were seen in minor subclones and lost at relapse; thus, such mutations can be secondary events.
  
  
  CONCLUSIONS
  Deep sequencing and SNP array analyses of T-ALL revealed lack of wUPIDs, a high proportion of sUPID9p targeting CDKN2A, NOTCH1 mutations in subclones, and recurrent mutations of genes involved in signaling transduction, epigenetic regulation, and transcription.
authors.affiliation: Department of Clinical Genetics, University and Regional Laboratories, Region Skåne, SE-221 85, Lund, Sweden. Kristina.Karrman@med.lu.se.|Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. Kristina.Karrman@med.lu.se.
authors.forename: Kristina
authors.initials: K
authors.lastname: Karrman
authors.affiliation: Department of Pediatrics, Skåne University Hospital, Lund University, Lund, Sweden. Anders.Castor@skane.se.
authors.forename: Anders
authors.initials: A
authors.lastname: Castor
authors.affiliation: Department of Pediatrics, Linköping University Hospital, Linköping, Sweden. Mikael.Behrendtz@lio.se.
authors.forename: Mikael
authors.initials: M
authors.lastname: Behrendtz
authors.affiliation: Department of Medical Biosciences, Clinical Genetics, Umeå University, Umeå, Sweden. Erik.Forestier@medbio.umu.se.
authors.forename: Erik
authors.initials: E
authors.lastname: Forestier
authors.affiliation: Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. Linda.Olsson@med.lu.se.
authors.forename: Linda
authors.initials: L
authors.lastname: Olsson
authors.affiliation: Department of Pathology, University and Regional Laboratories, Region Skåne, Lund, Sweden. Mats.Ehinger@skane.se.
authors.forename: Mats
authors.initials: M
authors.lastname: Ehinger
authors.affiliation: Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. Andrea.Biloglav@med.lu.se.
authors.forename: Andrea
authors.initials: A
authors.lastname: Biloglav
authors.affiliation: Department of Clinical Genetics, University and Regional Laboratories, Region Skåne, SE-221 85, Lund, Sweden. Thoas.Fioretos@med.lu.se.|Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. Thoas.Fioretos@med.lu.se.
authors.forename: Thoas
authors.initials: T
authors.lastname: Fioretos
authors.affiliation: Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. Kajsa.Paulsson@med.lu.se.
authors.forename: Kajsa
authors.initials: K
authors.lastname: Paulsson
authors.affiliation: Department of Clinical Genetics, University and Regional Laboratories, Region Skåne, SE-221 85, Lund, Sweden. Bertil.Johansson@med.lu.se.|Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. Bertil.Johansson@med.lu.se.
authors.forename: Bertil
authors.initials: B
authors.lastname: Johansson
mesh_terms: D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D020641:Polymorphism, Single Nucleotide; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics; D051881:Receptor, Notch1 / Q000235:genetics*; D024182:Uniparental Disomy
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1