title: Association between acquired uniparental disomy and homozygous gene mutation in acute myeloid leukemias.
abstract: Genome-wide single nucleotide polymorphism analysis has revealed large-scale cryptic regions of acquired homozygosity in the form of segmental uniparental disomy in approximately 20% of acute myeloid leukemias. We have investigated whether such regions, which are the consequence of mitotic recombination, contain homozygous mutations in genes known to be mutational targets in leukemia. In 7 of 13 cases with uniparental disomy, we identified concurrent homozygous mutations at four distinct loci (WT1, FLT3, CEBPA, and RUNX1). This implies that mutation precedes mitotic recombination which acts as a "second hit" responsible for removal of the remaining wild-type allele, as has recently been shown for the JAK2 gene in myeloproliferative disorders.
authors.affiliation: Cancer Research UK Medical Oncology Laboratory, Barts and the Royal London School of Medicine, Queen Mary College, London, United Kingdom.
authors.forename: Jude
authors.initials: J
authors.lastname: Fitzgibbon
authors.forename: Lan-Lan
authors.initials: LL
authors.lastname: Smith
authors.forename: Manoj
authors.initials: M
authors.lastname: Raghavan
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Smith
authors.forename: Silvana
authors.initials: S
authors.lastname: Debernardi
authors.forename: Spyros
authors.initials: S
authors.lastname: Skoulakis
authors.forename: Debra
authors.initials: D
authors.lastname: Lillington
authors.forename: T Andrew
authors.initials: TA
authors.lastname: Lister
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Young
mesh_terms: D000208:Acute Disease; D001483:Base Sequence; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D016162:Genes, Wilms Tumor; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics*; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D024182:Uniparental Disomy; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D050676:Core Binding Factor Alpha 2 Subunit; C493728:RUNX1 protein, human; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3