Rose-Zerilli, Matthew, Gibson, Jane, Wang, Jun, Tapper, Wi, Davis, Zadie, Parker, Helen, Larrayoz, Marta, McCarthy, Helen, Walewska, Renata, Forster, Jade, Gardiner, Anne, Steele, Andrew, Chelala, Claude, Ennis, Sarah, Collins, Andrew, Oakes, Christopher, Oscier, David and Strefford, Jonathan (2016) Longitudinal copy number, whole exome and targeted deep sequencing of 'good risk' IGHV-mutated CLL patients with progressive disease. Leukemia, 30 (6), 1301-1310. (doi:10.1038/leu.2016.10). (PMID:26847028)
Abstract
Disease progression in IGHV-M CLL with 'good-risk' cytogenetics is frequently associated with co-evolution of 'poor risk' driver mutations and DNA methylation changes.Drug resistance in IGHV-M CLL may be consequent upon the emergence of an IGHV-U cloneThe biological features of IGHV-M CLL responsible for disease progression are still poorly understood. We undertook a longitudinal study close to diagnosis, pre-treatment and post relapse in thirteen 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 ten have required therapy. Using cytogenetics, FISH, genome-wide DNA methylation and copy number analysis together with whole exome, targeted deep- and Sanger sequencing, at diagnosis we identified mutations in established CLL driver genes in nine (69%), non-coding mutations (PAX5 enhancer region) in three, and genomic complexity in two patients. Branching evolutionary trajectories predominated (n=9/13), revealing intra-tumoural epi- and genetic heterogeneity and sub-clonal competition prior to 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.Leukemia accepted article preview online, 05 February 2016. doi:10.1038/leu.2016.10.
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