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Whole-genome sequencing of chronic lymphocytic leukaemia reveals distinct differences in the mutational landscape between IgHV^mut and IgHV^unmut subgroups.

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 IgHV^mut and IgHV^unmut 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 IgHV^unmut CLL in IKZF3, SAMHD1,PAX5 and BIRC3. Finally, we show that IgHV^unmut CLL is dominated by coding mutations in driver genes and an aging signature, whereas IgHV^mut 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.

SUBMITTER: Burns A

PROVIDER: S-EPMC5808074 | biostudies-literature |

REPOSITORIES: biostudies-literature

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High CXCR3 on Leukemic Cells Distinguishes IgHV mut from IgHV unmut in Chronic Lymphocytic Leukemia: Evidence from CD5high and CD5low Clones.

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