title: Whole-genome sequencing reveals activation-induced cytidine deaminase signatures during indolent chronic lymphocytic leukaemia evolution.
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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.|Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kasar
authors.affiliation: Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: J
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.|Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: R
authors.initials: R
authors.lastname: Improgo
authors.affiliation: Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: G
authors.initials: G
authors.lastname: Tiao
authors.affiliation: Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: P
authors.initials: P
authors.lastname: Polak
authors.affiliation: Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: N
authors.initials: N
authors.lastname: Haradhvala
authors.affiliation: Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Lawrence
authors.affiliation: Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: A
authors.initials: A
authors.lastname: Kiezun
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Fernandes
authors.affiliation: Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: S
authors.initials: S
authors.lastname: Bahl
authors.affiliation: Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: C
authors.initials: C
authors.lastname: Sougnez
authors.affiliation: Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: S
authors.initials: S
authors.lastname: Gabriel
authors.affiliation: Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: E S
authors.initials: ES
authors.lastname: Lander
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: H T
authors.initials: HT
authors.lastname: Kim
authors.affiliation: Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.|Department of Pathology and Cancer Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.|Department of Pathology, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: G
authors.initials: G
authors.lastname: Getz
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.|Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Brown
mesh_terms: D000375:Aging / Q000235:genetics; D005075:Biological Evolution; D015331:Cohort Studies; D003564:Cytidine Deaminase / Q000235:genetics* / Q000378:metabolism; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology* / Q000235:genetics; D009154:Mutation; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase