title: Constitutional trisomy 8p11.21-q11.21 mosaicism: a germline alteration predisposing to myeloid leukaemia.
abstract: Juvenile myelomonocytic leukaemia (JMML) is a unique myeloproliferative disorder of early childhood. Frequently, mutations in NRAS, KRAS, PTPN11, NF1 or CBL are found in these patients. Monosomy 7 is the most common cytogenetic aberration. To identify submicroscopic genomic copy number alterations, 20 JMML samples were analysed by comparative genomic hybridization. Ten out of 20 samples displayed additional submicroscopic alterations. In two patients, an almost identical gain of chromosome 8 was identified. In both patients, fluorescence in situ hybridization confirmed a constitutional partial trisomy 8 mosaic (cT8M). A survey on 27 cT8M patients with neoplasms showed that 21 had myeloid malignancies, and five of these had a JMML. Notably, the region gained in our cases is the smallest gain of chromosome 8 reported in cT8M cases with malignancies so far. Our results dramatically reduce the critical region to 8p11.21q11.21 harbouring 31 protein coding genes and two non-coding RNAs, e.g. MYST3, IKBKB, UBE2V2, GOLGA7, FNTA and MIR486--a finding with potential implications for the role of somatic trisomy 8 in myeloid malignancies. Further investigations are required to more comprehensively determine how constitutional partial trisomy 8 mosaicisms may contribute to leukaemogenesis in different mutational subtypes of JMML and other myeloid malignancies.
authors.affiliation: Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Ripperger
authors.forename: Marcel
authors.initials: M
authors.lastname: Tauscher
authors.forename: Inka
authors.initials: I
authors.lastname: Praulich
authors.forename: Brigitte
authors.initials: B
authors.lastname: Pabst
authors.forename: Andrea
authors.initials: A
authors.lastname: Teigler-Schlegel
authors.forename: Allen
authors.initials: A
authors.lastname: Yeoh
authors.forename: Gudrun
authors.initials: G
authors.lastname: Göhring
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schlegelberger
authors.forename: Christian
authors.initials: C
authors.lastname: Flotho
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Niemeyer
authors.forename: Doris
authors.initials: D
authors.lastname: Steinemann
mesh_terms: D002872:Chromosome Deletion; D002897:Chromosomes, Human, Pair 7; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D020440:Gene Duplication; D015973:Gene Expression Regulation, Leukemic; D052138:Genes, Neoplasm; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D054429:Leukemia, Myelomonocytic, Juvenile / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics; D009030:Mosaicism; D014314:Trisomy
chemical_list: C560945:MIRN486 microRNA, human; D035683:MicroRNAs