Over the past few years, several large-scale studies using next-generation sequencing (NGS) of whole-genomes (WGS) and whole-exomes (WES) have defined the mutational landscape of chronic lymphocytic leukemia (CLL) []. NGS studies have also revealed the clonal heterogeneity in CLL and showed that clonal evolution contributes to the variability in clinical course among CLL patients []. Clonal evolution is considered a key condition in CLL progression and relapse after treatment. Most CLL cases are diagnosed during the inactive disease phase, genetic aberrations’ underlying progress in CLL activity leading to the need for therapy are poorly understood and should be explored. A large number of frequently mutated genes have been identified and several putative driver mutations likely to confer selective growth advantage to CLL tumor cells have been proposed []. In addition, clonal shifts between paired treatment-naïve and relapsed CLL samples have been reported due to pre-existing subclone expansion under therapeutic pressure, demonstrating that clonal evolution likely underlies CLL relapse []. Nevertheless, there are still a limited amount of longitudinal WES studies analyzing consecutive CLL samples before treatment intervegntion []. The acquisition of driver mutations accompanied by selectively neutral passenger changes during disease prior to therapy influence is therefore poorly documented. Here, WES was performed on consecutive treatment-naïve samples of CLL patients from three groups with different disease course: Active disease (AD) group: patients with an active disease before the second analyzed time-point (TP2); Stable disease (SD) group: cases with a period of stable phase after diagnosis followed by progression within 3 years after; and Indolent disease (ID) group: those with a long-term stable indolent disease. Moreover, we applied a novel integrative bioinformatics tool called “Cancer Genome Interpreter” to identify driver mutations [].

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