Whole-genome sequencing of chronic lymphocytic leukaemia reveals distinct differences in the mutational landscape between IgHVmut and IgHVunmut subgroups.
Date
2018-02-01ICR Author
Author
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
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Aged
Aged, 80 and over
Cytidine Deaminase
Enhancer Elements, Genetic
Female
Genes, Immunoglobulin Heavy Chain
Humans
Immunoglobulin Heavy Chains
Immunoglobulin Variable Region
Leukemia, Lymphocytic, Chronic, B-Cell
Male
Middle Aged
Mutation
Promoter Regions, Genetic
Proto-Oncogene Proteins
SAM Domain and HD Domain-Containing Protein 1
Whole Genome Sequencing
Research team
Cancer Genomics
Language
eng
Date accepted
2017-05-17
License start date
2018-02-01
Citation
Leukemia, 2018, 32 (2), pp. 332 - 342
Publisher
NATURE PUBLISHING GROUP