title: Genomic characterization implicates iAMP21 as a likely primary genetic event in childhood B-cell precursor acute lymphoblastic leukemia.
abstract: Intrachromosomal amplification of chromosome 21 (iAMP21) defines a distinct subgroup of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) that has a dismal outcome when treated with standard therapy. For improved diagnosis and risk stratification, the initiating genetic events need to be elucidated. To investigate the genetic basis of BCP-ALL, genomes of 94 iAMP21 patients were interrogated by arrays, FISH, and multiplex ligation-dependent probe amplification. Most copy number alterations targeted chromosome 21, reinforcing the complexity of this chromosome. The common region of amplification on chromosome 21 was refined to a 5.1-mb region that included RUNX1, miR-802, and genes mapping to the Down syndrome critical region. Recurrent abnormalities affecting genes in key pathways were identified: IKZF1 (22%), CDKN2A/B (17%), PAX5 (8%), ETV6 (19%), and RB1 (37%). Investigation of clonal architecture provided evidence that these abnormalities, and P2RY8-CRLF2, were secondary to chromosome 21 rearrangements. Patient outcome was uniformly poor with standard therapy irrespective of the presence or absence of these changes. This study has provided evidence that chromosome 21 instability is the only anomaly among those so far investigated that is common to all iAMP21 patients, and therefore the initiating event is likely to be found among the complex structural rearrangements of this abnormal chromosome.
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Vikki
authors.initials: V
authors.lastname: Rand
authors.forename: Helen
authors.initials: H
authors.lastname: Parker
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Russell
authors.forename: Claire
authors.initials: C
authors.lastname: Schwab
authors.forename: Hannah
authors.initials: H
authors.lastname: Ensor
authors.forename: Julie
authors.initials: J
authors.lastname: Irving
authors.forename: Lisa
authors.initials: L
authors.lastname: Jones
authors.forename: Dino
authors.initials: D
authors.lastname: Masic
authors.forename: Lynne
authors.initials: L
authors.lastname: Minto
authors.forename: Heather
authors.initials: H
authors.lastname: Morrison
authors.forename: Sarra
authors.initials: S
authors.lastname: Ryan
authors.forename: Hazel
authors.initials: H
authors.lastname: Robinson
authors.forename: Paul
authors.initials: P
authors.lastname: Sinclair
authors.forename: Anthony V
authors.initials: AV
authors.lastname: Moorman
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Strefford
authors.forename: Christine J
authors.initials: CJ
authors.lastname: Harrison
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D002891:Chromosomes, Human, Pair 21; D015331:Cohort Studies; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D006801:Humans; D053612:Janus Kinases / Q000235:genetics; D008297:Male; D009154:Mutation; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D055815:Young Adult
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; C493728:RUNX1 protein, human; D053612:Janus Kinases