Whole-Genome Scanning by Array Comparative Genomic Hybridization as a Clinical Tool for Risk Assessment in Chronic Lymphocytic Leukemia

Abstract

Array-based comparative genomic hybridization (array CGH) provides a powerful method for simultaneous genome-wide scanning and prognostic marker assessment in chronic lymphocytic leukemia (CLL). In the current study, commercially available bacterial artificial chromosome and oligonucleotide array CGH platforms were used to identify chromosomal alterations of prognostic significance in 174 CLL cases. Tumor genomes were initially analyzed by bacterial artificial chromosome array CGH followed by confirmation and breakpoint mapping using oligonucleotide arrays. Genomic changes involving loci currently interrogated by fluorescence in situ hybridization (FISH) panels were detected in 155 cases (89%) at expected frequencies: 13q14 loss (47%), trisomy 12 (13%), 11q loss (11%), 6q loss (7.5%), and 17p loss (4.6%). Genomic instability was the second most commonly identified alteration of prognostic significance with three or more alterations involving loci not interrogated by FISH panels identified in 37 CLL cases (21%). A subset of 48 CLL cases analyzed by six-probe FISH panels (288 total hybridizations) was concordant with array CGH results for 275 hybridizations (95.5%); 13 hybridizations (4.5%) were discordant because of clonal populations that comprised less than 30% of the sample. Array CGH is a powerful, cost-effective tool for genome-wide risk assessment in the clinical evaluation of CLL.

Atypical 11q deletions identified by array CGH may be missed by FISH panels for prognostic markers in chronic lymphocytic leukemia

“…In a number of recent studies evaluating the use of array CGH as a clinical tool for genomic alteration detection in CLL, array CGH results have exhibited a high concordance with parallel FISH studies, except when FISH aberrations are present in less than B25-30% of the cells. [9][10][11][12][13][14] In a recent report from our laboratory, we analyzed 174 cases of CLL by bacterial artificial chromosome (BAC)-based array CGH and found that we could identify correctly the aberrations identified by FISH 96% of the time. 12 The discordant results were because of small clonal cell populations that comprised o25-30% of the total sample.…”

“…[9][10][11][12][13][14] In a recent report from our laboratory, we analyzed 174 cases of CLL by bacterial artificial chromosome (BAC)-based array CGH and found that we could identify correctly the aberrations identified by FISH 96% of the time. 12 The discordant results were because of small clonal cell populations that comprised o25-30% of the total sample. Interestingly, two CLL cases with cryptic (B1 Mb) 13q14 deletions detected by array CGH were missed by both of the 13q14 region FISH probes used in this study.…”

“…The ZW10, PLZF and TSLC1 genes were also deleted in all of the other 19 cases exhibiting 11q deletions in a recent CLL array CGH study from our laboratory. 11,12 Further studies are needed to evaluate the possible association of losses of these genes with higher-risk subsets of CLL. However, this study suggests that the poor prognosis associated with 11q deletions in CLL may be due to alterations in the expression of a number of genes that contribute to cell growth control and genome integrity rather than owing to only a single gene.…”

“…[6][7][8] Recently, array comparative genomic hybridization (array CGH) has been gaining acceptance as a diagnostic tool that can also be applied to detect genomic gains and losses of prognostic importance in CLL, because of the advantages afforded by simultaneous genome-wide and locus-specific assessment of the leukemia with a single assay. [9][10][11][12][13][14] Array CGH is well suited for the identification of genomic alterations of prognostic importance in CLL, because the most common and important aberrations are comprised of genomic losses and gains, whereas chromosomal translocations are relatively rare. Although translocations do occur in CLL, their prognostic significance is currently controversial.…”

The rewards and challenges of array-based karyotyping for clinical oncology applications

“…However, regional copy number Editorial heterogeneity can be due to either clonal evolution or the existence of two separate clones in the sample (Figure 2b), and neither FISH nor array-based karyotyping can distinguish between the two possibilities. Regional copy number heterogeneity has been reported by others 5,13 and it can be either terminal, as in this example, or interstitial. The ability to detect the genetic heterogeneity illuminated by array-based karyotyping is exciting, but the clinical relevance of this heterogeneityFin genomic length, UPD or regional copy numberFhas yet to be vetted.…”