Genomic complexity identifies patients with aggressive chronic lymphocytic leukemia - PubMed (original) (raw)

Genomic complexity identifies patients with aggressive chronic lymphocytic leukemia

Lisa Kujawski et al. Blood. 2008.

Abstract

Chronic lymphocytic leukemia (CLL) has a variable clinical course. Presence of specific genomic aberrations has been shown to impact survival outcomes and can help categorize CLL into clinically distinct subtypes. We studied 178 CLL patients enrolled in a prospective study at the University of Michigan, of whom 139 and 39 were previously untreated and previously treated, respectively. We obtained unbiased, high-density, genome-wide measurements of subchromosomal copy number changes in highly purified DNA from sorted CD19(+) cells and buccal cells using the Affymetrix 50kXbaI SNP array platform (Santa Clara, CA). Genomic complexity scores were derived and correlated with the surrogate clinical end points time to first therapy (TTFT) and time to subsequent therapy (TTST): measures of disease aggressiveness and/or therapy efficaciousness. In univariate analysis, progressively increasing complexity scores in previously untreated CLL patients identified patients with short TTFT at high significance levels. Similarly, TTST was significantly shorter in pretreated patients with high as opposed to low genomic complexity. In multivariate analysis, genomic complexity emerged as an independent risk factor for short TTFT and TTST. Finally, algorithmic subchromosomal complexity determination was developed, facilitating automation and future routine clinical application of CLL whole-genome analysis.

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Figures

Figure 1

Figure 1

The 50k SNP array platform can detect single copy chromosomal differences in the CLL genome with high sensitivity and specificity. DNA from FACS-sorted CD19+ cells and buccal cells was extracted and prepared for hybridization to the 50kXbaI SNP chips as per manufacturer's recommendation. Copy number estimates for each SNP position were calculated using dChipSNP and displayed for all SNP positions, for all patients, for the indicated chromosomes. Copy losses are displayed with blue colors; copy gains, with red colors. The physical position of SNPs is not linear along the displayed portions of the chromosome. (A) Chromosome X. Color-coded copy number estimates are grouped by the known sex of the patients. Red asterisks indicate females with LOH at chromosome X indicating loss. The estimated copy numbers for all SNP positions for CLL no. 105 are displayed along the entire chromosome to the right of the X chromosome display, with the red line indicating the 2N state. (B) Chromosome 12. All patients with FISH results positive for trisomy 12 are grouped on the left of the image. The estimated copy numbers for all SNP positions for CLL no. 143 is shown along the entire chromosome to the right of the chromosome 12 display, with the red line indicating the 2N state. Sporadic subchromosomal copy losses are encircled with red ovals. The approximate position of the clinically used trisomy 12 FISH probe is indicated.

Figure 2

Figure 2

The visual complexity score based on losses predicts for a short time to first therapy in univariate analysis in a cohort of previously untreated CLL patients (Kaplan-Meier plots). The numbers of subchromosomal genomic losses for each patient were determined using 50kXbaI SNP array technology as described in “Derivation of a genomic complexity score, Visual methods” and the mean number of losses as determined by 2 independent observers correlated against the clinical end point time to first therapy (TTFT). Depicted are Kaplan-Meier estimates (A-F) for increasing complexity score cutoffs (eg, < N vs ≥ N lesions per genome) and TTFT estimates (months).

Figure 3

Figure 3

The visual complexity score based on losses predicts for a short time to subsequent therapy in univariate analysis in a cohort of previously treated CLL patients (Kaplan-Meier plots). The numbers of subchromosomal losses were determined using 50kXbaI SNP array technology for each patient as described in “Derivation of a genomic complexity score, Visual method,” and the mean number of losses as determined by 2 independent observers correlated against the clinical end point time to subsequent therapy (TTST). Depicted are Kaplan-Meier estimates (A-F) for increasing complexity score cutoffs (eg, < N vs ≥ N lesions per genome) and TTST estimates (months).

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