Back to Search
Start Over
Longitudinal copy number, whole exome and targeted deep sequencing of 'good risk' IGHV-mutated CLL patients with progressive disease.
- Source :
-
Leukemia [Leukemia] 2016 Jun; Vol. 30 (6), pp. 1301-10. Date of Electronic Publication: 2016 Feb 05. - Publication Year :
- 2016
-
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.
- Subjects :
- Adolescent
Adult
Aged
Clone Cells
Cytogenetic Analysis
Disease Progression
Genetic Heterogeneity
High-Throughput Nucleotide Sequencing
Humans
Longitudinal Studies
Middle Aged
Risk
Young Adult
Exome genetics
Gene Dosage
Immunoglobulin Heavy Chains genetics
Leukemia, Lymphocytic, Chronic, B-Cell genetics
Mutation
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5551
- Volume :
- 30
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Leukemia
- Publication Type :
- Academic Journal
- Accession number :
- 26847028
- Full Text :
- https://doi.org/10.1038/leu.2016.10