High Resolution Genome-Wide Array-Based Comparative Genome Hybridization Reveals Cryptic Chromosome Changes in AML and MDS Cases with Trisomy 8 as the Sole Cytogenetic Aberration.

Although trisomy 8 as the sole chromosome aberration is the most common numerical abnormality in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), next to nothing is known about its pathogenetic effects. Considering that +8 is a frequent secondary change in AML and MDS, cryptic - and possibly primary - genetic aberrations may occur in cases with trisomy 8 as the apparently single anomaly. To date, however, no such hidden anomalies have been reported. We performed a high resolution genome-wide array-based comparative genome hybridization (array CGH) analysis of ten AML/MDS cases with isolated +8, using an array set containing >30,000 BAC and PAC clones. Array CGH revealed intra-chromosomal imbalances, not corresponding to known genomic polymorphisms, in 5/10 cases, comprising ten duplications and hemizygous deletions ranging in size from 0.5 to 2.2 Mb. Most notably, a 1.8 Mb hemizygous deletion at 7p14.1, which had occurred prior to the +8, was identified in one MDS transforming to AML. Furthermore, a hemizygous deletion at 12p13.2, including ETV6 , was present in one case. The remaining eight imbalances involved more than 40 genes. The present results show that cryptic genetic abnormalities are frequent in trisomy 8-positive AML and MDS cases and that +8 as the sole cytogenetic aberration is not always the primary genetic event.

[1]  D. Pinkel,et al.  Mantle-cell lymphoma genotypes identified with CGH to BAC microarrays define a leukemic subgroup of disease and predict patient outcome. , 2005, Blood.

[2]  M. Shipitsin,et al.  Activation of RalA is critical for Ras-induced tumorigenesis of human cells. , 2005, Cancer cell.

[3]  M. Qumsiyeh,et al.  Rapid array‐based genomic characterization of a subtle structural abnormality: A patient with psychosis and der(18)t(5;18)(p14.1;p11.23) , 2005, American journal of medical genetics. Part A.

[4]  C. Preudhomme,et al.  CEBPA point mutations in hematological malignancies , 2005, Leukemia.

[5]  W. Hiddemann,et al.  Genomic gains and losses influence expression levels of genes located within the affected regions: a study on acute myeloid leukemias with trisomy 8, 11, or 13, monosomy 7, or deletion 5q , 2005, Leukemia.

[6]  Adanma Ndubuizu,et al.  The ALX Src Homology 2 Domain Is Both Necessary and Sufficient to Inhibit T Cell receptor/CD28-mediated Up-regulation of RE/AP* , 2004, Journal of Biological Chemistry.

[7]  Kenny Q. Ye,et al.  Large-Scale Copy Number Polymorphism in the Human Genome , 2004, Science.

[8]  N. Nowak,et al.  Application of bacterial artificial chromosome array-based comparative genomic hybridization and spectral karyotyping to the analysis of glioblastoma multiforme. , 2004, Cancer genetics and cytogenetics.

[9]  J. Veltman,et al.  Genome-wide array-based comparative genomic hybridization reveals multiple amplification targets and novel homozygous deletions in pancreatic carcinoma cell lines. , 2004, Cancer research.

[10]  D. Gary Gilliland,et al.  The FIP1L1-PDGFRα fusion tyrosine kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia: implications for diagnosis, classification, and management , 2004 .

[11]  T. Kyo,et al.  High incidence of somatic mutations in the AML1/RUNX1 gene in myelodysplastic syndrome and low blast percentage myeloid leukemia with myelodysplasia. , 2004, Blood.

[12]  Bradley P. Coe,et al.  A tiling resolution DNA microarray with complete coverage of the human genome , 2004, Nature Genetics.

[13]  Sarah Barber,et al.  A set of BAC clones spanning the human genome. , 2004, Nucleic acids research.

[14]  T. Liehr,et al.  Trisomy 8 as the sole chromosomal aberration in myelocytic malignancies: a comprehensive molecular cytogenetic analysis reveals no cryptic aberrations. , 2003, Cancer genetics and cytogenetics.

[15]  Jaakko Astola,et al.  CGH-Plotter: MATLAB toolbox for CGH-data analysis , 2003, Bioinform..

[16]  I. Hanamura,et al.  Inactivation of the E3/LAPTm5 gene by chromosomal rearrangement and DNA methylation in human multiple myeloma , 2003, Leukemia.

[17]  H. Tanke,et al.  Trisomy 8 as the sole chromosomal aberration in myelocytic malignancies: a multicolor and locus-specific fluorescence in situ hybridization study. , 2003, Cancer genetics and cytogenetics.

[18]  A. Venditti,et al.  Comparison between conventional banding analysis and FISH screening with an AML-specific set of probes in 260 patients. , 2003, The hematology journal : the official journal of the European Haematology Association.

[19]  S. Gruvberger,et al.  BioArray Software Environment (BASE): a platform for comprehensive management and analysis of microarray data , 2002, Genome Biology.

[20]  H. Gundacker,et al.  Impact of trisomy 8 (+8) on clinical presentation, treatment response, and survival in acute myeloid leukemia: a Southwest Oncology Group study. , 2002, Blood.

[21]  K. Anderson,et al.  Involvement and functional impairment of the CD34(+)CD38(-)Thy-1(+) hematopoietic stem cell pool in myelodysplastic syndromes with trisomy 8. , 2002, Blood.

[22]  S. Dudoit,et al.  Normalization for cDNA microarray data: a robust composite method addressing single and multiple slide systematic variation. , 2002, Nucleic acids research.

[23]  F. Locatelli,et al.  Trisomy 8 in myelodysplasia and acute leukemia is constitutional in 15–20% of cases , 2002, Genes, chromosomes & cancer.

[24]  B. Johansson,et al.  The incidence of trisomy 8 as a sole chromosomal aberration in myeloid malignancies varies in relation to gender, age, prior iatrogenic genotoxic exposure, and morphology. , 2001, Cancer genetics and cytogenetics.

[25]  A. Genevière,et al.  A new subfamily of high molecular mass CDC2-related kinases with PITAI/VRE motifs. , 2000, Biochemical and biophysical research communications.

[26]  B. Johansson,et al.  Acute myeloid leukemia and clonal chromosome aberrations in relation to past exposure to organic solvents. , 2000, Scandinavian journal of work, environment & health.

[27]  Cervera,et al.  Incidence, characterization and prognostic significance of chromosomal abnormalities in 640 patients with primary myelodysplastic syndromes , 2000, British journal of haematology.

[28]  K Wheatley,et al.  The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children's Leukaemia Working Parties. , 1998, Blood.

[29]  W. Kuo,et al.  High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays , 1998, Nature Genetics.

[30]  M. Höglund,et al.  Deletions of CDKN1B and ETV6 in acute myeloid leukemia and myelodysplastic syndromes without cytogenetic evidence of 12p abnormalities , 1997, Genes, chromosomes & cancer.