Evidence-based genomic diagnosis characterized chromosomal and cryptic imbalances in 30 elderly patients with myelodysplastic syndrome and acute myeloid leukemia

Abstract

BackgroundTo evaluate the clinical validity of genome-wide oligonucleotide array comparative genomic hybridization (aCGH) for detecting somatic abnormalities, we have applied this genomic analysis to 30 cases (13 MDS and 17 AML) with clonal chromosomal abnormalities detected in more than 50% of analyzed metaphase cells.ResultsThe aCGH detected all numerical chromosomal gains and losses from the mainline clones and 113 copy number alterations (CNAs) ranging from 0.257 to 102.519 megabases (Mb). Clinically significant recurrent deletions of 5q (involving the RPS14 gene), 12p12.3 (ETV6 gene), 17p13 (TP53 gene), 17q11.2 (NF1 gene) and 20q, double minutes containing the MYC gene and segmental amplification involving the MLL gene were further characterized with defined breakpoints and gene contents. Genomic features of microdeletions at 17q11.2 were confirmed by FISH using targeted BAC clones. The aCGH also defined break points in a derivative chromosome 6, der(6)t(3;6)(q21.3;p22.2), and an isodicentric X chromosome. However, chromosomally observed sideline clonal abnormalities in five cases were not detected by aCGH.ConclusionsOur data indicated that an integrated cytogenomic analysis will be a better diagnostic scheme to delineate genomic contents of chromosomal and cryptic abnormalities in patients with MDS and AML. An evidence-based approach to interpret somatic genomic findings was proposed.

ETV6 deletion is a common additional abnormality in patients with myelodysplastic syndromes or acute myeloid leukemia and monosomy 7

“…Outside of two cohorts with chromosome 12 abnormalities 8,9 and one case series with complex karyotypes,…”

“…7,8 Detection of FLT3 internal tandem duplications (ITD) and tyrosine kinase domain (TKD) mutations was performed using the FLT3 Mutation Assay (InVivoScribe Technologies, San Diego, CA, USA) according to the manufacturer's protocol. Informed consent was obtained from all individuals and the study was approved by the institutional review board of the Medical University of Graz, Austria.…”

Identification of clinically important chromosomal aberrations in acute myeloid leukemia by array-based comparative genomic hybridization

“…Cytogenetic data in AML patients contribute to diagnosis and provide prognostic parameters useful for disease stratification and treatment evaluation [1,2]. Based on cytogenetic results, most often derived by using conventional karyotypic analysis or by fluorescence in situ hybridization, AML patients can be stratified into “favorable,” “intermediate,” and “poor” or “unfavorable” prognostic groups.…”

Array CGH in Human Leukemia: From Somatics to Genetics

“…The average number of copy number alterations in patients was found to be comparable for pediatric AML [Radtke et al, 2009] and adult AML [Walter et al, 2009] (2.34 and 2.38 copy number alterations per genome, respectively) in studies that used paired normal and tumor DNA. Copy number alterations have been reported in 15-40% of AML patients with normal karyotype, in 40-90% of MDS/AML patients with abnormal clones and in almost 100% of cases with complex chromosomal abnormalities [Rucker et al, 2006;Suela et al, 2007;Tyybakinoja et al, 2007a;Starczynow ski et al, 2008;Akagi et al, 2009;Radtke et al, 2009;Walter et al, 2009;Slovak et al, 2010;Bajaj et al, 2011].…”