title: Longitudinal copy number, whole exome and targeted deep sequencing of 'good risk' IGHV-mutated CLL patients with progressive disease.
abstract: The biological features of IGHV-M chronic lymphocytic leukemia responsible for disease progression are still poorly understood. We undertook a longitudinal study close to diagnosis, pre-treatment and post relapse in 13 patients presenting with cMBL or Stage A disease and good-risk biomarkers (IGHV-M genes, no del(17p) or del(11q) and low CD38 expression) who nevertheless developed progressive disease, of whom 10 have required therapy. Using cytogenetics, fluorescence in situ hybridisation, genome-wide DNA methylation and copy number analysis together with whole exome, targeted deep- and Sanger sequencing at diagnosis, we identified mutations in established chronic lymphocytic leukemia driver genes in nine patients (69%), non-coding mutations (PAX5 enhancer region) in three patients and genomic complexity in two patients. Branching evolutionary trajectories predominated (n=9/13), revealing intra-tumoural epi- and genetic heterogeneity and sub-clonal competition before therapy. Of the patients subsequently requiring treatment, two had sub-clonal TP53 mutations that would not be detected by standard methodologies, three qualified for the very-low-risk category defined by integrated mutational and cytogenetic analysis and yet had established or putative driver mutations and one patient developed progressive, therapy-refractory disease associated with the emergence of an IGHV-U clone. These data suggest that extended genomic and immunogenetic screening may have clinical utility in patients with apparent good-risk disease.
authors: Academic Unit of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
authors: M J J
authors: MJ
authors: Rose-Zerilli
authors: Centre for Biological Sciences, Faculty of Natural and Environmental Studies, University of Southampton, Southampton, UK.
authors: J
authors: J
authors: Gibson
authors: Bioinformatics Unit, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors: J
authors: J
authors: Wang
authors: Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK.
authors: W
authors: W
authors: Tapper
authors: Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK.
authors: Z
authors: Z
authors: Davis
authors: Academic Unit of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
authors: H
authors: H
authors: Parker
authors: Academic Unit of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
authors: M
authors: M
authors: Larrayoz
authors: Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK.
authors: H
authors: H
authors: McCarthy
authors: Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK.
authors: R
authors: R
authors: Walewska
authors: Academic Unit of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
authors: J
authors: J
authors: Forster
authors: Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK.
authors: A
authors: A
authors: Gardiner
authors: Academic Unit of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
authors: A J
authors: AJ
authors: Steele
authors: Bioinformatics Unit, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors: C
authors: C
authors: Chelala
authors: Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK.
authors: S
authors: S
authors: Ennis
authors: Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK.
authors: A
authors: A
authors: Collins
authors: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, USA.
authors: C C
authors: CC
authors: Oakes
authors: Academic Unit of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.|Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK.
authors: D G
authors: DG
authors: Oscier
authors: Academic Unit of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
authors: J C
authors: JC
authors: Strefford
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002999:Clone Cells; D020732:Cytogenetic Analysis; D018450:Disease Progression; D059472:Exome / Q000235:genetics*; D018628:Gene Dosage; D018740:Genetic Heterogeneity; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D008137:Longitudinal Studies; D008875:Middle Aged; D009154:Mutation; D012306:Risk; D055815:Young Adult
chemical_list: D007143:Immunoglobulin Heavy Chains