Whole-genome sequencing reveals activation-induced cytidine deaminase signatures during indolent chronic lymphocytic leukaemia evolution

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 thes...

Full description

Bibliographic Details
Main Authors:	Kasar, S., Kim, J., Improgo, R., Tiao, G., Polak, P., Haradhvala, N., Lawrence, M. S., Kiezun, A., Fernandes, S. M., Bahl, S., Sougnez, C., Gabriel, S., Lander, E. S., Kim, H. T., Getz, G., Brown, J. R.
Format:	Online
Language:	English
Published:	Nature Publishing Group 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4686820/

id	pubmed-4686820
recordtype	oai_dc
spelling	pubmed-46868202016-01-07 Whole-genome sequencing reveals activation-induced cytidine deaminase signatures during indolent chronic lymphocytic leukaemia evolution Kasar, S. Kim, J. Improgo, R. Tiao, G. Polak, P. Haradhvala, N. Lawrence, M. S. Kiezun, A. Fernandes, S. M. Bahl, S. Sougnez, C. Gabriel, S. Lander, E. S. Kim, H. T. Getz, G. Brown, J. R. Article 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. Nature Publishing Group 2015-12-07 /pmc/articles/PMC4686820/ /pubmed/26638776 http://dx.doi.org/10.1038/ncomms9866 Text en Copyright © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Kasar, S. Kim, J. Improgo, R. Tiao, G. Polak, P. Haradhvala, N. Lawrence, M. S. Kiezun, A. Fernandes, S. M. Bahl, S. Sougnez, C. Gabriel, S. Lander, E. S. Kim, H. T. Getz, G. Brown, J. R.
spellingShingle	Kasar, S. Kim, J. Improgo, R. Tiao, G. Polak, P. Haradhvala, N. Lawrence, M. S. Kiezun, A. Fernandes, S. M. Bahl, S. Sougnez, C. Gabriel, S. Lander, E. S. Kim, H. T. Getz, G. Brown, J. R. Whole-genome sequencing reveals activation-induced cytidine deaminase signatures during indolent chronic lymphocytic leukaemia evolution
author_facet	Kasar, S. Kim, J. Improgo, R. Tiao, G. Polak, P. Haradhvala, N. Lawrence, M. S. Kiezun, A. Fernandes, S. M. Bahl, S. Sougnez, C. Gabriel, S. Lander, E. S. Kim, H. T. Getz, G. Brown, J. R.
author_sort	Kasar, S.
title	Whole-genome sequencing reveals activation-induced cytidine deaminase signatures during indolent chronic lymphocytic leukaemia evolution
title_short	Whole-genome sequencing reveals activation-induced cytidine deaminase signatures during indolent chronic lymphocytic leukaemia evolution
title_full	Whole-genome sequencing reveals activation-induced cytidine deaminase signatures during indolent chronic lymphocytic leukaemia evolution
title_fullStr	Whole-genome sequencing reveals activation-induced cytidine deaminase signatures during indolent chronic lymphocytic leukaemia evolution
title_full_unstemmed	Whole-genome sequencing reveals activation-induced cytidine deaminase signatures during indolent chronic lymphocytic leukaemia evolution
title_sort	whole-genome sequencing reveals activation-induced cytidine deaminase signatures during indolent chronic lymphocytic leukaemia evolution
description	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.
publisher	Nature Publishing Group
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4686820/
_version_	1613515327228870656

Whole-genome sequencing reveals activation-induced cytidine deaminase signatures during indolent chronic lymphocytic leukaemia evolution

Similar Items