Mutational signature analysis of chronic lymphocytic leukemia uncovering genomic patterns and prognostic implications.

Abstract

Objective: To identify the mutational signature(s) for patients with diagnosed chronic lymphocytic leukemia (CLL) and their correlation with clinical and genetic classifications.

Methods: All CLL samples sequenced on several versions of OncoPanel, from 2013 to 2022, were examined (n = 209). All variants produced by the next-generation sequencing pipeline, before review, were obtained for these samples. After the exclusion of likely germline polymorphisms, mutational signatures were generated. De novo mutational signatures were extracted and correlated with clinical and genetic data.

Results: Most somatic mutations were found in chromosome 14 (within ADAM6). Somatic mutation signatures analysis revealed a prominent endogenous mutational process, which predominantly led to C-to-T single base substitutions (SBSs). Two novel de novo SBS signatures were identified, weighted by the SBS84 signature, that correlated with somatically hypermutated and unmutated status, respectively, with significant disease heterogeneity. A notable 13.3% of the cohort exhibited the SBS42 signature, suggesting a link to occupational haloalkane exposure, representing a potential new environmental risk factor for CLL.

Conclusions: The de novo SBS signatures were identified as being associated with IGHV status, highlighting significant disease heterogeneity that belies the more categorical and limited traditional risk stratification methods. Also, a novel association was made between haloalkane exposure signature and CLL.