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  • 1
    Keywords: Germany ; THERAPY ; FOLLOW-UP ; NETWORK ; DISEASE ; DISEASES ; NEW-YORK ; GENE ; HYBRIDIZATION ; SAMPLE ; SAMPLES ; TIME ; PATIENT ; COMPLEX ; COMPLEXES ; MARKER ; chromosome ; bone marrow ; BONE-MARROW ; early detection ; IN-SITU ; AMPLIFICATION ; COMPARATIVE GENOMIC HYBRIDIZATION ; CHROMOSOMAL-ABERRATIONS ; leukemia ; ABERRATIONS ; ACUTE LYMPHOBLASTIC-LEUKEMIA ; IN-SITU HYBRIDIZATION ; INSTABILITY ; FAILURE ; FLUORESCENCE ; fluorescence in situ hybridization ; MANAGEMENT ; ACUTE MYELOGENOUS LEUKEMIA ; in situ hybridization ; SINGLE ; DISORDERS ; TRANSITION ; CHROMOSOMAL INSTABILITY ; USA ; genomic ; FANCONI-ANEMIA ; congenital ; aberration ; chromosomal aberration ; AML1 ; congenital neutropenia ; inherited bone marrow failure syndromes ; leukemogenesis ; NEUTROPENIA ; SHWACHMAN-DIAMOND-SYNDROME
    Abstract: As chromosomal instability may contribute to leukemogenesis in patients with congenital bone marrow failure (CBMF) disorders, it was the aim of this study to characterize chromosomally aberrant clones that arise during the clinical course of disease by means of R-banding and fluorescence in situ hybridization (FISH) analyses. In addition, multicolor-FISH and array-comparative genomic hybridization (CGH) were applied to characterize clonal chromosome aberrations in more detail. Between January 2004 and December 2005, we prospectively analyzed 90 samples of 73 patients with proven or suspected CBMF disorders enrolled in a German Study Network of CBMF diseases. Clonal aberrations could be identified in four of 73 patients examined. In one child with congenital thrombocytopenia, Jacobsen syndrome [del(11)(q24)c] was diagnosed, and thus a CBMF could be excluded. In a girl with Shwachman-Diamond syndrome, two independent clones, one with an isochromosome i(7)(q10), another with a complex aberrant karyotype, were identified. Simultaneously, transition into a myelodysplastic syndrome (MDS) occurred. The brother, who was also afflicted with Shwachman-Diamond syndrome, showed an isochromosome i(7q) as a single aberration. In the fourth patient with severe congenital neutropenia, an add(21)(q22) marker containing a low-level amplification of the AML1 gene was identified at the time point of transition into acute myelogenous leukemia (AML). In summary, we suggest that follow-up of patients with CBMF using chromosome and FISH analyses will be helpful for the early detection of transition into MDS or AML and thus should be an integral part of the clinical management of these patients
    Type of Publication: Journal article published
    PubMed ID: 17653548
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  • 2
    Keywords: CANCER ; CELLS ; SURVIVAL ; tumor ; TUMOR-CELLS ; CELL ; Germany ; COHORT ; DISEASE ; POPULATION ; DISTINCT ; GENE ; GENOME ; HYBRIDIZATION ; PATIENT ; COMPLEX ; COMPLEXES ; DNA ; QUALITY ; CONTRAST ; bone marrow ; BONE-MARROW ; RECOGNITION ; DELETION ; PROGRESSION ; COMPARATIVE GENOMIC HYBRIDIZATION ; COPY NUMBER ; ARRAYS ; NUMBER ; genetics ; ACUTE LYMPHOBLASTIC-LEUKEMIA ; DELETIONS ; PCR ; FISH ; POPULATIONS ; FREQUENT ; RECURRENT ; IMBALANCES ; CHROMOSOMAL IMBALANCES ; MYELODYSPLASTIC SYNDROME ; HETEROGENEITY ; ONCOLOGY ; CHILDHOOD ; TUMOR-SUPPRESSOR ; SUPPRESSOR GENE ; ACUTE MYELOID-LEUKEMIA ; development ; TIME QUANTITATIVE PCR ; methods ; PROFILES ; BONE ; PROFILE ; tumor suppressor ; Genetic ; CNV ; CONTRIBUTE ; MICRODELETIONS ; CHRONIC MYELOMONOCYTIC LEUKEMIA ; COMPLEX ABERRANT KARYOTYPE ; COPY NUMBER ALTERATIONS ; DISPLACEMENT AMPLIFICATION ; OLIGONUCLEOTIDE ARRAY-CGH ; RISK MYELODYSPLASTIC SYNDROMES
    Abstract: To evaluate whether copy number alterations (CNAs) are present that may contribute to disease development and/or progression of childhood myelodysplastic syndromes (MDS), 36 pediatric MDS patients were analyzed using array-based comparative genome hybridization (aCGH). In addition to monosomy 7, the most frequent chromosome aberration in childhood MDS, novel recurrent CNAs were detected. They included a loss of 3p14.3-p12.3, which contains the putative tumor suppressor gene FHIT, a loss of 7p21.3-p15.3, a loss of 9q33.3-q34.3 (D184) and microdeletions in 17p11.2, 6q23 containing MYB, and 17p13 containing TP53. In this small patient cohort, patients without CNA, patients with monosomy 7 only and patients with one CNA in addition to monosomy 7 did not differ in their survival. As expected, all patients with complex karyotypes, including two patients with deletions of TP53, died. A challenge inherent to aCGH analysis of MDS is the low percentage of tumor cells. We evaluated several approaches to overcome this limitation. Genomic profiles from isolated granulocytes were of higher quality than those from bone marrow mononuclear cells. Decreased breakpoint calling stringency increased recognition of CNAs present in small clonal populations. However, further analysis using a custom-designed array showed that these CNAs often did not confirm the findings from 244k arrays. In contrast, constitutional CNVs were reliably detected on both arrays. Moreover, aCGH on amplified DNA from distinct myeloid clusters is a new approach to determine CNAs in small subpopulations. Our results clearly emphasize the need to verify array-CGH results by independent methods like FISH or quantitative PCR. (C) 2010 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 20589934
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