Abstract
Patients with chromosome 13q deletion or normal cytogenetics represent the majority of
chronic lymphocytic leukaemia (CLL) cases, yet have relatively few driver mutations. To
better understand their genomic landscape, here we perform whole-genome sequencing on a
cohort of patients enriched with these cytogenetic characteristics. Mutations in known CLL
drivers are seen in only 33% of this cohort, and associated with normal cytogenetics and
unmutated IGHV. The most commonly mutated gene in our cohort, IGLL5, shows a mutational
pattern suggestive of activation-induced cytidine deaminase (AID) activity. Unsupervised
analysis of mutational signatures demonstrates the activities of canonical AID (c-AID),
leading to clustered mutations near active transcriptional start sites; non-canonical AID
(nc-AID), leading to genome-wide non-clustered mutations, and an ageing signature
responsible for most mutations. Using mutation clonality to infer time of onset, we find that
while ageing and c-AID activities are ongoing, nc-AID-associated mutations likely occur
earlier in tumour evolution.
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