Abstract
To evaluate the clinical utility, diagnostic yield and rationale of integrating microarray analysis in the clinical diagnosis of hematological malignancies in comparison with classical chromosome karyotyping/fluorescence in situ hybridization (FISH). G-banded chromosome analysis, FISH and microarray studies using customized CGH and CGH+SNP designs were performed on 27 samples from patients with hematological malignancies. A comprehensive comparison of the results obtained by three methods was conducted to evaluate benefits and limitations of these techniques for clinical diagnosis. Overall, 89.7% of chromosomal abnormalities identified by karyotyping/FISH studies were also detectable by microarray. Among 183 acquired copy number alterations (CNAs) identified by microarray, 94 were additional findings revealed in 14 cases (52%), and at least 30% of CNAs were in genomic regions of diagnostic/prognostic significance. Approximately 30% of novel alterations detected by microarray were >20 Mb in size. Balanced abnormalities were not detected by microarray; however, of the 19 apparently "balanced" rearrangements, 55% (6/11) of recurrent and 13% (1/8) of non-recurrent translocations had alterations at the breakpoints discovered by microarray. Microarray technology enables accurate, cost-effective and time-efficient whole-genome analysis at a resolution significantly higher than that of conventional karyotyping and FISH. Array-CGH showed advantage in identification of cryptic imbalances and detection of clonal aberrations in population of non-dividing cancer cells and samples with poor chromosome morphology. The integration of microarray analysis into the cytogenetic diagnosis of hematologic malignancies has the potential to improve patient management by providing clinicians with additional disease specific and potentially clinically actionable genomic alterations.
Highlights
Among 183 acquired copy number alterations (CNAs) identified by microarray, 94 were additional findings revealed in 14 cases (52%), and at least 30% of CNAs were in genomic regions of diagnostic/prognostic significance
FISH enables the rapid detection of: 1) fusion genes amenable to targeted therapy (e.g., PML-RARA, ABL1-BCR); 2) other recurrent cytogenetic abnormalities of diagnostic or prognostic importance that may be present in quiescent cells, including both chromosomal rearrange ments and copy number abnormalities; 3) submicroscopic copy number changes of clinical significance, such as deletions involving TP53 and ATM; 4) relatively low-level mosaicism for clonal aberrations by evaluation of a large population of interphase cells; and 5) may facilitate the characterization of complex chromosome rearrangements identified by G-banded analysis
Twenty-seven specimens were analyzed for DNA copy number variations (CNVs) using either the comparative genomic hybridization (CGH) or CGH+single nucleotide polymorphism (SNP) microarray design
Summary
Classical cytogenetic analysis (G-banding) plays a critical role in the diagnosis, prognosis and treatment planning of hematologic malignancies [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16], and enables the detection of large genomic alterations, including aneusomies, balanced and unbalanced chromosomal rearrangements of at least 10–20 Mb in size, and www.impactjournals.com/oncotarget mosaicism. Fluorescence in situ hybridization (FISH) has proven invaluable as an ancillary technique for the identification of clinically significant chromosomal aberrations, as FISH can be performed on metaphase or non-dividing interphase cells, and can detect genomic abnormalities with a resolution from 150 to 900 kb, depending on the probe size. FISH enables the rapid detection of: 1) fusion genes amenable to targeted therapy (e.g., PML-RARA, ABL1-BCR); 2) other recurrent cytogenetic abnormalities of diagnostic or prognostic importance that may be present in quiescent cells, including both chromosomal rearrange ments and copy number abnormalities; 3) submicroscopic copy number changes of clinical significance, such as deletions involving TP53 and ATM; 4) relatively low-level mosaicism for clonal aberrations by evaluation of a large population of interphase cells; and 5) may facilitate the characterization of complex chromosome rearrangements identified by G-banded analysis. FISH may yield false negative results in cases where genomic imbalances are smaller than the size of a FISH probe or chromosomal rearrangements are complex; or false positive results when two fluorescent signals co-localize due to viewing a threedimensional nucleus in two dimensions
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