Genomic Profiling of Chronic Lymphocytic Leukemia Identifies Novel Genetic Subtypes.
CLL is the most common leukemia in the Western world and displays considerable clinical heterogeneity. Genetic approaches to elucidate defects in CLL genomes have resulted in the identification of recurrent chromosomal abnormalities with prognostic importance. A genome-wide high-density unbiased view of chromosomal copy number changes or loss of heterozygosity (LOH) may allow for further refinements of genomics-based risk prognostication. We have conducted a genomic profiling study using 50KSNP-oligonucleotide arrays (Affymetrix) on FACS-sorted CD19+ cells and paired buccal DNA from 120 patients with typical CLL (CD5+/CD23+) at various stages of presentation enrolled in a clinical translational protocol. We have found novel genetic subtypes, including novel regions of recurrent LOH and chromosomal copy loss on chromosomes 3p, 14q and 18p at frequencies of 3–6%. Fine mapping of the clinically important regions del(6q), del(11q), del(13q14) and del(17p) suggests molecular heterogeneity of these lesions. Anatomic criteria suggest existence of multiple distinct subtypes of del13q14. Furthermore, the clinically important del(17p) is associated with almost uniform deletion of most of 17p, occasionally displays copy-neutral LOH (undetectable by FISH) with p53 mutations and occurs without p53 mutations in a subset of patients as previously reported. Finally, using a genome-wide composite genomic instability score of copy gains and losses we found a subset of CLL cases (18%) with high genomic instability values (greater than 2 lesions per genome). These findings may have implications for CLL risk-adapted therapies.
Malek, SN; Kujawski, LA; Erba, HP; Kaminski, MS; Jakubowiak, A; Dressel, A; Saddler, CM; Shedden, KA; Ouillette, PD
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