Whole-genome sequencing reveals activation-induced cytidine deaminase signatures during indolent chronic lymphocytic leukaemia evolution
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Lander_Whole-genome.pdf
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Author(s)
Kasar, S.
Kim, J.
Improgo, R.
Tiao, G.
Polak, P.
Haradhvala, N.
Lawrence, M. S.
Kiezun, A.
Fernandes, S. M.
Bahl, S.
Date Issued
December 2015
Journal
Nature Communications
Publisher
Nature Publishing Group
Citation
Kasar, S. et al. “Whole-Genome Sequencing Reveals Activation-Induced Cytidine Deaminase Signatures during Indolent Chronic Lymphocytic Leukaemia Evolution.” Nature Communications 6 (2015): 8866. © 2015 Macmillan Publishers Limited
Version
Final published version
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
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Creative Commons Attribution 4.0 International License
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DOI of Published Version
https://doi.org/10.1038/ncomms9866
