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

S Kasar,S Bahl,G Tiao,R Improgo,S M Fernandes,H T Kim,J R Brown,S Gabriel,N Haradhvala,E S Lander,G Getz,M S Lawrence,A Kiezun,J Kim,P Polak,C Sougnez

doi:10.1038/ncomms9866

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.

Highlights

Patients with chromosome 13q deletion or normal cytogenetics represent the majority of chronic lymphocytic leukaemia (CLL) cases, yet have relatively few driver mutations
Deletions in this locus have been frequently reported in a variety of B-cell neoplasms including CLL, they have not been detected in normal B cells, indicating that they are not a by-product of normal immunoglobulin rearrangements[14,15]
In summary, we describe here the results of whole-genome sequencing of a CLL cohort comprised of low-risk cytogenetic subgroups in which we find that a small subset have complex rearrangements that may be associated with more aggressive disease, while a significant number have only 13q deletion as an obvious CLL driver

Summary

Introduction

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. Relatively higher sequencing costs have limited the number of whole-genome studies (n 1⁄4 4, Puente et al.[3]; n 1⁄4 28, Alexandrov et al.[4], with only signature analysis reported without detailed cohort description) and to date, most studies involved larger exome data sets, which were likely the major driver of the primary findings. Developed techniques using Non-negative Matrix Factorization (NMF)[5] to perform unsupervised analysis of somatic mutation data has enabled the unbiased discovery of genome-wide mutational patterns in multiple tumour types[4,6,7]. In the context of known CLL and AID biology, our results support a model of differential activities of the two AID signatures and the ageing signature throughout tumour evolution

Methods

Results

Conclusion