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  • 1
    Keywords: CANCER ; EXPRESSION ; CELL ; Germany ; IN-VIVO ; THERAPY ; DISEASE ; RISK ; GENE ; GENE-EXPRESSION ; GENES ; PATIENT ; ASSOCIATION ; DELETION ; COMPARATIVE GENOMIC HYBRIDIZATION ; gene expression ; DIFFERENCE ; NUMBER ; genetics ; leukemia ; DELETIONS ; REGION ; REGIONS ; HIGH-RISK ; CHILDREN ; CHRONIC MYELOGENOUS LEUKEMIA ; PROGNOSTIC FACTOR ; heredity ; ONCOLOGY ; CHILDHOOD ; THERAPIES ; PROGNOSTIC IMPACT ; CELL LYMPHOMA ; PROGNOSTIC-FACTOR ; USA ; LOSSES ; ARRAY-CGH ; PROFILE ; DERIVATIVE CHROMOSOME-9 ; EARLY TREATMENT RESPONSE ; INTRACHROMOSOMAL AMPLIFICATION ; TRANSLOCATION T(1/19)
    Abstract: In vivo response to initial therapy, as assessed by determination of minimal residual disease (MRD) after 5 and 12 weeks of treatment, has evolved as a strong prognostic factor in children with acute lymphoblastic leukemia (ALL) treated according to the BFM regime. Individual treatment response may be influenced by copy number alterations (CNA) leading to altered gene expression. We aimed to evaluate CNA using high-resolution array-comparative genomic hybridization (array-CGH) in different treatment-response groups. Leukemic genomic profiles of 25 standard risk (MRD-SR) and 25 high risk (MRD-HR) patients were compared. CNAs were found in 46/50 patients (92%). The most significant difference was a gain of 1q23-qter because of an unbalanced t(1; 19), found in 10/25 MRD-SR patients, but in none of the MRD-HR patients (P 〈 0.001). The most frequent Cl in the MRD-HR group were deletions of genomic regions harboring the immunoglobulin genes (1g), e.g., 2p11.2 in 60% of MRD-HR compared to 28% of MRD-SR (P = 0.045). Combining all 1g loci, significantly more MRD-HR than MRD-SR patients displayed deletions (17:8 patients, P = 0.02). Frequency of other CNAs, such as loss of 9p21 or gains of 21q, did not differ strongly between the two patient groups. This is the first study evaluating the clinical significance of CNA as detected by array-CGH in childhood ALL and the first to suggest that such analyses may provide clinically important data. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat. (C) 2008 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 18311775
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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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