Genomic complexity in chronic lymphocytic leukemia

In this issue of Blood, Kujawski and colleagues report that genetic complexity in CLL is associated with aggressive disease. These investigators examine the DNA of the leukemia cells from 178 CLL patients for loss or gain of genomic material using arrays capable of detecting SNPs.

A single nucleotide polymorphism (SNP) is a polymorphic variation at a single site in DNA, of which approximately 10 million have been identified in the human genome. Each person has many different SNPs that together reflect a unique DNA sequence. A DNA microarray with thousands of immobilized allele-specific oligonucleotides specific for such sequences can probe the genomic DNA for genetic polymorphisms. Such SNP arrays also can evaluate for loss of heterozygosity (LOH), a form of allelic imbalance resulting from the complete loss or increased copy number of one allele relative to the other. Using SNP-array technology, other investigators have identified LOH in many solid tumors and hematological malignancies, including chronic lymphocytic leukemia (CLL).^1,2  Kujawski et al go one step further to report that the degree of LOH complexity found in CLL cells via use of SNP arrays bears a strong relationship to the relative aggressiveness of this disease.

Prior studies using conventional techniques have found that patients with complex cytogenetics-containing CLL cells have a relatively poor prognosis.^3,4  Certain CLL cell genetic abnormalities, such as deletions in the short arm of chromosome 17 or in long arm of chromosome 11, are independent predictors of adverse outcome. Increasingly, though, there is recognition that the overall complexity of the genetic aberrations found in CLL cells is an adverse prognostic marker independent of the specific abnormalities detected.^5-8  The propensity of a CLL cell population to develop such complex genetic abnormalities might be associated with characteristics that adversely influence outcome and/or allow for secondary and tertiary genetic changes. These changes could also adversely affect the response to therapy or overall survival. In either case, the use of SNP arrays to discern such genetic complexity might offer advantages over more conventional techniques, as this method does not require complex in vitro culture conditions or use of more limited sets of probes that could yield false-negative results.

However, there are some caveats to this approach. SNP arrays are insensitive to detecting balanced translocations or genetic aberrations which are present in less than about a quarter of the cells examined. As such, the use of SNP arrays in the clinical setting might require methods for isolating leukemia cells that are not currently available to most clinical pathology laboratories. In addition, SNP arrays might be less sensitive than fluorescence in situ hybridization techniques in detecting intraclonal genetic changes that sometimes are found during CLL clonal evolution.⁹  Nevertheless, the current study affirms the importance of focusing attention on the somatic genomic alterations involved in CLL pathogenesis and progression, reminding us once again that CLL, like all cancers, is truly a genetic disease.