Abstract
Chronic lymphocytic leukemia (CLL) is the most frequent lymphoproliferative syndrome in Western countries, and it is characterized by recurrent large genomic rearrangements. During the last decades, array techniques have expanded our knowledge about CLL’s karyotypic aberrations. The advent of large sequencing databases expanded our knowledge cancer genomics to an unprecedented resolution and enabled the detection of small-scale structural aberrations in the cancer genome. In this study, we have performed exome-sequencing-based copy number aberration (CNA) and loss of heterozygosity (LOH) analysis in order to detect new recurrent structural aberrations. We describe 54 recurrent focal CNAs enriched in cancer-related pathways, and their association with gene expression and clinical evolution. Furthermore, we discovered recurrent large copy number neutral LOH events affecting key driver genes, and we recapitulate most of the large CNAs that characterize the CLL genome. These results provide “proof-of-concept” evidence supporting the existence of new genes involved in the pathogenesis of CLL.
Highlights
Chronic lymphocytic leukemia (CLL) is the most frequent lymphoproliferative disease in Western populations, and it is characterized by its clinical and genetic heterogeneity. Döhner et al (2000) described the widely used cytogenetic classification of CLL based on the most prevalent chromosomal aberrations in the CLL genome (Döhner et al, 2000), that is, trisomy 12 and deletions in 13q14.2–14.3, 11q22.3, and 17p13.1
We discovered recurrent large copy number neutral loss of heterozygosity (LOH) events affecting key driver genes, and we recapitulate most of the large copy number aberrations (CNAs) that characterize the CLL genome
We identified 54 recurrent focal CNAs in the CLL genome
Summary
Chronic lymphocytic leukemia (CLL) is the most frequent lymphoproliferative disease in Western populations, and it is characterized by its clinical and genetic heterogeneity. Döhner et al (2000) described the widely used cytogenetic classification of CLL based on the most prevalent chromosomal aberrations in the CLL genome (Döhner et al, 2000), that is, trisomy 12 and deletions in 13q14.2–14.3, 11q22.3, and 17p13.1. Döhner et al (2000) described the widely used cytogenetic classification of CLL based on the most prevalent chromosomal aberrations in the CLL genome (Döhner et al, 2000), that is, trisomy 12 and deletions in 13q14.2–14.3, 11q22.3, and 17p13.1. A wealth of genomic and epigenomic modulators of CLL’s clinical aggressivity have been discovered (Nadeu et al, 2018), such as point mutations in NOTCH1, SF3B1, ATM, TP53, and POT1 and the absence of somatic hypermutation at the IGHV locus. It has been observed that copy number aberrations (CNAs) in CLL genomes tend to be acquired early in disease evolution and usually remain stable, whereas the mutational heterogeneity can increase (Nadeu et al, 2018). Mounting evidence indicates that the accumulation of these cytogenomic events modulates CLL proliferation and clinical aggressivity to a great extent (Raponi et al, 2018; Gruber et al, 2019), acting as drivers of genomic complexity
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
