title: Copy number neutral loss of heterozygosity at 17p and homozygous mutations of TP53 are associated with complex chromosomal aberrations in patients newly diagnosed with myelodysplastic syndromes.
abstract: Complex karyotypes are seen in approximately 20% of patients with myelodysplastic syndromes (MDS) and are associated with a high risk of transformation to acute myeloid leukemia and poor outcomes in patients. Copy number neutral loss of heterozygosity (CN-LOH, i.e., both copies of a chromosomal pair or their parts originate from one parent) might contribute to increased genomic instability in the bone-marrow cells of patients with MDS. The pathological potential of CN-LOH, which arises as a clonal aberration in a proportion of somatic cells, consists of tumor suppressor gene and oncogene homozygous mutations. The aim of our study was to evaluate the frequency of CN-LOH at 17p in bone-marrow cells of newly diagnosed MDS patients with complex chromosomal aberrations and to assess its correlation with mutations in the TP53 gene (17p13.1). CN-LOH was detected in 40 chromosomal regions in 21 (29%) of 72 patients analyzed. The changes in 27 of the 40 regions identified were sporadic. The most common finding was CN-LOH of the short arm of chromosome 17, which was detected in 13 (18%) of 72 patients. A mutational analysis confirmed the homozygous mutation of TP53 in all CN-LOH 17p patients, among which two frameshift mutations are not registered in the International Agency for Research on Cancer TP53 Database. CN-LOH 17p correlated with aggressive disease (median overall survival 4 months) and was strongly associated with a complex karyotype in the cohort studied, which might cause rapid disease progression in high-risk MDS. No other CN-LOH region previously recorded in MDS or AML patients (1p, 4q, 7q, 11q, 13q, 19q, 21q) was detected in our cohort of patients with complex karyotype examined at the diagnosis of MDS. The LOH region appeared to be balanced (i.e., with no DNA copy number change) when examined with conventional and molecular cytogenetic methods. Therefore, a microarray that detects single-nucleotide polymorphisms is an ideal method with which to identify and further characterize CN-LOH. Our data should specify the prognosis and should lead to the identification of potential targets for therapeutic interventions.
authors: Center of Oncocytogenetics, Institute of Medical Biochemistry and Laboratory Diagnostics, General University Hospital and First Faculty of Medicine, Charles University in Prague, Czech Republic. Electronic address: karla.svobodova@vfn.cz.
authors: Karla
authors: K
authors: Svobodova
authors: Center of Oncocytogenetics, Institute of Medical Biochemistry and Laboratory Diagnostics, General University Hospital and First Faculty of Medicine, Charles University in Prague, Czech Republic.
authors: Zuzana
authors: Z
authors: Zemanova
authors: Center of Oncocytogenetics, Institute of Medical Biochemistry and Laboratory Diagnostics, General University Hospital and First Faculty of Medicine, Charles University in Prague, Czech Republic.
authors: Halka
authors: H
authors: Lhotska
authors: Center of Oncocytogenetics, Institute of Medical Biochemistry and Laboratory Diagnostics, General University Hospital and First Faculty of Medicine, Charles University in Prague, Czech Republic.
authors: Milena
authors: M
authors: Novakova
authors: Center of Oncocytogenetics, Institute of Medical Biochemistry and Laboratory Diagnostics, General University Hospital and First Faculty of Medicine, Charles University in Prague, Czech Republic.
authors: Lucie
authors: L
authors: Podskalska
authors: Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
authors: Monika
authors: M
authors: Belickova
authors: Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
authors: Jana
authors: J
authors: Brezinova
authors: Center of Oncocytogenetics, Institute of Medical Biochemistry and Laboratory Diagnostics, General University Hospital and First Faculty of Medicine, Charles University in Prague, Czech Republic; Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
authors: Iveta
authors: I
authors: Sarova
authors: Center of Oncocytogenetics, Institute of Medical Biochemistry and Laboratory Diagnostics, General University Hospital and First Faculty of Medicine, Charles University in Prague, Czech Republic.
authors: Silvia
authors: S
authors: Izakova
authors: Center of Oncocytogenetics, Institute of Medical Biochemistry and Laboratory Diagnostics, General University Hospital and First Faculty of Medicine, Charles University in Prague, Czech Republic.
authors: Libuse
authors: L
authors: Lizcova
authors: Center of Oncocytogenetics, Institute of Medical Biochemistry and Laboratory Diagnostics, General University Hospital and First Faculty of Medicine, Charles University in Prague, Czech Republic.
authors: Adela
authors: A
authors: Berkova
authors: First Medical Department, General University Hospital and First Faculty of Medicine, Charles University in Prague, Czech Republic.
authors: Magda
authors: M
authors: Siskova
authors: First Medical Department, General University Hospital and First Faculty of Medicine, Charles University in Prague, Czech Republic.
authors: Anna
authors: A
authors: Jonasova
authors: Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
authors: Jaroslav
authors: J
authors: Cermak
authors: Center of Oncocytogenetics, Institute of Medical Biochemistry and Laboratory Diagnostics, General University Hospital and First Faculty of Medicine, Charles University in Prague, Czech Republic; Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
authors: Kyra
authors: K
authors: Michalova
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002869:Chromosome Aberrations; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D005260:Female; D018628:Gene Dosage; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D019656:Loss of Heterozygosity / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
keywords: Acquired uniparental disomy; Complex chromosomal aberration; Copy number neutral loss of heterozygosity; Mutation; Myelodysplastic syndromes; TP53 gene