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Blood, 1 September 2008, Vol. 112, No. 5, pp. 1550.
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NEOPLASIA
Comment on Kujawski et al, page 1993
Genomic complexity in chronic lymphocytic leukemia
Thomas J. Kipps
UNIVERSITY OF CALIFORNIA SAN DIEGO, MOORES CANCER CENTER
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.
Footnotes
Conflict-of-interest disclosure: The author declares no competing financial interests. 
REFERENCES
- Pfeifer D, Pantic M, Skatulla I, et al. Genome-wide analysis of DNA copy number changes and LOH in CLL using high-density SNP arrays. Blood. 2007;109:1202–1210.[Abstract/Free Full Text]
- Gunnarsson R, Staaf J, Jansson M, et al. Screening for copy-number alterations and loss of heterozygosity in chronic lymphocytic leukemia-A comparative study of four differently designed, high resolution microarray platforms. Genes Chromosomes Cancer. 2008;47:697–711.[CrossRef][Medline]
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- Juliusson G, Merup M. Cytogenetics in chronic lymphocytic leukemia. Semin Oncol. 1998;25:19–26.[Medline]
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- Dohner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000;343:1910–1916.[Abstract/Free Full Text]
- Dicker F, Schnittger S, Haferlach T, et al. Immunostimulatory oligonucleotide-induced metaphase cytogenetics detect chromosomal aberrations in 80% of CLL patients: A study of 132 CLL cases with correlation to FISH, IgVH status, and CD38 expression. Blood. 2006;108:3152–3160.[Abstract/Free Full Text]
- Mayr C, Speicher MR, Kofler DM, et al. Chromosomal translocations are associated with poor prognosis in chronic lymphocytic leukemia. Blood. 2006;107:742–751.[Abstract/Free Full Text]
- Van Den Neste E, Robin V, Francart J, et al. Chromosomal translocations independently predict treatment failure, treatment-free survival and overall survival in B-cell chronic lymphocytic leukemia patients treated with cladribine. Leukemia. 2007;21:1715–1722.[CrossRef][Medline]
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- Roos G, Krober A, Grabowski P, et al. Short telomeres are associated with genetic complexity, high-risk genomic aberrations, and short survival in chronic lymphocytic leukemia. Blood. 2008;111:2246–2252.[Abstract/Free Full Text]
- Stilgenbauer S, Sander S, Bullinger L, et al. Clonal evolution in chronic lymphocytic leukemia: acquisition of high-risk genomic aberrations associated with unmutated VH, resistance to therapy, and short survival. Haematologica. 2007;92:1242–1245.[Abstract/Free Full Text]
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Related Article in Blood Online:
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Genomic complexity identifies patients with aggressive chronic lymphocytic leukemia
- Lisa Kujawski, Peter Ouillette, Harry Erba, Chris Saddler, Andrzej Jakubowiak, Mark Kaminski, Kerby Shedden, and Sami N. Malek
Blood 2008 112: 1993-2003.
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