Next generation sequencing to identify novel genomic aberrations with relevance in CLL development and progression

Apart from larger chromosomal rearrangements and deletions, recurrent somatic gene mutations contribute to the pathogenesis and characteristics of CLL. Although mutations occur in significantly higher numbers in solid tumors, recent whole-genome sequencing of CLL samples resulted in a noteworthy number of about 1000 somatic mutations per tumor. As treatment-associated evolution of CLL cells is believed to contribute to relapse of disease and refractory CLL, our aim was to acquire and compare genome-wide mutations (whole genome and whole exome sequencing) in selected CLL cases at several time-points, that are (i) early onset of disease, (ii) at therapy indication, and (iii) after becoming refractory. This longitudinal approach allows for the identification of mutations that provide a fitness advantage for CLL cells and therefore drive disease progression. In cooperation with Prof. Stephan Stilgenbauer and Prof. Thorsten Zenz, 30 exomes and 4 genomes were analyzed so far and several known but also novel recurrent mutations were identified. Targeted re-sequencing of the genes of interest in larger cohorts of patients as well as functional studies evaluating the relevance of the detected mutations in CLL development and progression are planned in the future.

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