Detection of recurrent chromosomal defects in chronic lymphocytic leukemia/small lymphocytic lymphoma: Innovations and applications

The study of recurrent chromosomal defects has yielded profound insights into the biology of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) that have translated into improved prognostic precision and changes in management. These advances have relied on interphase fluorescent in situ hybridization (FISH) to examine non-dividing CLL cells. A landmark report of FISH analysis of CLL cells with eight probes published in 2000 established a clinically applicable hierarchical prognostic risk stratification method [1]. However, FISH analysis of CLL cells provides a limited view of the genetic defects in CLL. A more comprehensive and higher resolution method of detecting genomic defects in CLL cells is likely to provide additional insights into the biology of CLL, improve prognostic precision, and guide more precisely targeted therapy. Genome wide analysis with array-based comparative genomic hybridization (aCGH) and single nucleotide polymorphism (aSNP) assays provide an exciting new approach to detection of novel genetic defects in CLL [2–5]. aCGH and aSNP analyses can detect defects in CLL cells that are not included in current FISH probe sets, and can also detect lesions that are below the level of resolution of FISH analysis. However, currently available aCGH and aSNP cytogenetic assays can usually only detect defects that are present in at least 20–30% of the tested cells compared to 5–10% for FISH analysis [2,6], and array analysis cannot readily identify subclones or clonal evolution. In addition, the cost and technical complexity of aCGH and aSNP assays currently limit their utility in clinical laboratories. However, these array-based assays are very useful discovery tools in detecting novel genomic defects in CLL, measuring the heterogeneity of these defects, and determining if defects occur in multiple genes which are functionally related. In this issue of the Journal, Jarasova et al. report the results of an CGH study analyzing gain of genetic material by duplication of the short arm of chromosome 2 (2pþ) in a subset of patients with CLL [7]. Their low density aCGH shows acquisition of a common approximately 64 Mb region of 2p (p13– p25) in all cases studied. This large region of 2p includes the loci for NMYC, REL, and ALK, genes which the authors consider to be of particular interest in the etiology of CLL. However, they provide no new data on the expression of these genes in the affected CLL cells to support their hypothesis. The study also provides a detailed description of the karyotypic abnormalities involving 2p detected in these patients. As expected for a population of patients with CLL with intermediate to advanced clinical stage disease, most of the patients with 2pþ have other additional markers of poor risk disease. This study thus contributes to our knowledge of 2pþ in CLL by providing a more detailed genetic map of the additional chromosomal material in these cells and suggesting genes of interest for future study. The study by Jarasova et al. does not provide conclusive data supporting their recommendation of routine testing for 2pþ using a FISH probe for NMYC in patients with CLL. The NMYC probe could fail to detect some patients with CLL with 2pþ. In three published array cytogenetics studies, a subset of CLL patients with 2pþ exhibited small