The biology and clinical significance of acquired genomic copy number aberrations and recurrent gene mutations in chronic lymphocytic leukemia

Abstract

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world and remains incurable with conventional chemotherapy treatment approaches. CLL as a disease entity is defined by a relatively parsimonious set of diagnostic criteria and therefore likely constitutes an umbrella term for multiple related illnesses. Of the enduring fundamental biological processes that affect the biology and clinical behavior of CLL, few are as central to the pathogenesis of CLL as recurrent acquired genomic copy number aberrations (aCNA) and recurrent gene mutations. Here, a state-of-the-art overview of the pathological anatomy of the CLL genome is presented, including detailed descriptions of the anatomy of aCNA and gene mutations. Data from SNP array profiling and large-scale sequencing of large CLL cohorts, as well as stimulated karyotyping, are discussed. This review is organized by discussions of the anatomy, underlying pathomechanisms and clinical significance of individual genomic lesions and recurrent gene mutations. Finally, gaps in knowledge regarding the biological and clinical effects of recurrent genomic aberrations or gene mutations on CLL are outlined to provide critical stimuli for future research.

Figure 1

Genomic copy number heatmap displays of chromosome 13q of 255 CLL cases ranked by the position of centromeric 13q14 deletion break points. (a) Copy number heatmap displays for paired DNA samples based on SNP 6.0 array profiling were generated using dChipSNP. Left panel: CD3 + or buccal DNA; right panel: CLL CD19 + DNA. Blue indicates copy loss. Each column represents one patient. (b) Schemas of various del13q14 in CLL: M, maternal chromosome; P, paternal chromosome. The approximate locations of selected genes (miR15a/16.1, DLEU7 and RB) are indicated. Deletions are indicated by blue bars.

Figure 2

(a) Genomic copy number heatmap displays of chromosome 17p of 255 CLL cases: copy number heatmap displays for paired DNA samples based on SNP 6.0 array profiling were generated using dChipSNP. Left panel: CD3 + or buccal DNA; right panel: CLL CD19 + DNA. Blue indicates copy loss, red indicates copy gain. Each column represents one patient. Lower panel: 17p-LOH; red arrows indicate cases with cnLOH-17p. (b) Schemas of del17p in relation to TP53 mutations and LOH at 17p in CLL: M, maternal chromosome; P, paternal chromosome. The approximate location of TP53 is indicated. Red bars indicate mutated TP53.

Figure 3

(a–h) Genomic copy number heatmap display of eight distinct recurrent aCNAs based on 255 CLL cases: Blue indicates copy loss, red indicates copy gain. Asterisks indicate an aCNA. Based on highly purified DNA from sorted CD19 + and CD3 + cells as described in Ouillette et al. (2011).