Analysis of the dynamics of copy number variation in Chronic Lymphocytic Leukemia: a longitudinal study

Introduction

Clonal evolution often follows chemotherapy in Chronic Lymphocytic Leukemia (CLL), and affect clinical outcome [1]. We investigated whether the selection of adaptive CLL clone(s) is a pre-requisite for the aggressive disease switch also in untreated CLLs. To this end we analysed in both stable (S-CLL) and progressive (P-CLL) untreated patients: 1)the number of aberrations which are gained or lost over time and 2)their rate of change over time. Then, we characterized 3)the genomic regions showing a significant different rate of change of CNV between groups.

Material and method

We analysed a longitudinal cohort of 27 untreated CLL patients with either stable (n=11) or progressive (n=16) disease over two clinical time points (median between time points: 980 days for S-CLL and 910 days for P-CLL) using Genome-Wide Human SNP Arrays 6. Copy number was detected by using Rawcopy package [2]. We defined new genomic segmentations to compare the copy number of each region at individual or group level. Finally, to determine the cut-off for amplification and deletion of the regions, we used different thresholds by inferring the percentage of cancer cells and the average ploidy of the analysed locus in the cancer cells.

Results and discussion

We found not significant differences between S-CLL and P-CLL in the percentage of gained and lost aberrations over time. Nevertheless, by considering the same gained or lost regions, we found a significant difference in the distribution of the slopes (p≤0.05, M-W test); specifically, we observed higher slopes, indicating higher rates of change, in P-CLL.

We also identified 167 regions showing a significant different slope (p≤0.01, M-W test) between S-CLL and P-CLL and able to divide the two groups by using a hierarchical clustering algorithm (p=0.0009, F test). Among those regions, several lies within the locus 2p11.2, and show an opposite trend between groups and a high rate of change over time (mean_slope= 2.6x10^-4 for S-CLL and -8.7x10^-4 for P-CLL), indicating that P-CLL, as opposed to S-CLL, are prone to select a clone having a deletion within the 2p11.2.

Conclusion

Our results highlight the importance of the copy number temporal evolution of aberrant regions. These findings suggest that the P-CLL patients evolve faster and are more likely to acquire new aberrant karyotype over time; this dynamic could be the pre-requisite for the subsequent selection of most adapted clone.

1)Landau et al,2013. Cell.

2)Mayrhofer et al,2016. Sci Rep.