Whole-genome sequencing of chronic lymphocytic leukaemia reveals distinct differences in the mutational landscape between IgHVmut and IgHVunmut subgroups.

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ICR Authors

Houlston, Richard

Authors

Burns, A
Alsolami, R
Becq, J
Stamatopoulos, B
Timbs, A
Bruce, D
Robbe, P
Vavoulis, D
Clifford, R
Cabes, M
Dreau, H
Taylor, J
Knight, SJL
Mansson, R
Bentley, D
Beekman, R
Martín-Subero, JI
Campo, E
Houlston, RS
Ridout, KE
Schuh, A

Document Type

Journal Article

Date

2018-02-01

Date Accepted

2017-05-17

Abstract

Chronic lymphocytic leukaemia (CLL) consists of two biologically and clinically distinct subtypes defined by the abundance of somatic hypermutation (SHM) affecting the Ig variable heavy-chain locus (IgHV). The molecular mechanisms underlying these subtypes are incompletely understood. Here, we present a comprehensive whole-genome sequencing analysis of somatically acquired genetic events from 46 CLL patients, including a systematic comparison of coding and non-coding single-nucleotide variants, copy number variants and structural variants, regions of kataegis and mutation signatures between IgHVmut and IgHVunmut subtypes. We demonstrate that one-quarter of non-coding mutations in regions of kataegis outside the Ig loci are located in genes relevant to CLL. We show that non-coding mutations in ATM may negatively impact on ATM expression and find non-coding and regulatory region mutations in TCL1A, and in IgHVunmut CLL in IKZF3, SAMHD1,PAX5 and BIRC3. Finally, we show that IgHVunmut CLL is dominated by coding mutations in driver genes and an aging signature, whereas IgHVmut CLL has a high incidence of promoter and enhancer mutations caused by aberrant activation-induced cytidine deaminase activity. Taken together, our data support the hypothesis that differences in clinical outcome and biological characteristics between the two subgroups might reflect differences in mutation distribution, incidence and distinct underlying mutagenic mechanisms.

Citation

Leukemia, 2018, 32 (2), pp. 332 - 342

DOI

10.1038/leu.2017.177

URI

https://repository.icr.ac.uk/handle/internal/5909

Rights

https://creativecommons.org/licenses/by-nc-nd/4.0/

Source Title

Leukemia

Publisher

NATURE PUBLISHING GROUP

ISSN

0887-6924

eISSN

1476-5551
1476-5551

Collections

Genetics and Epidemiology

Research Team

Cancer Genomics

Notes