Chronic lymphocytic leukaemia (CLL), the most frequent leukaemia in adults in Western countries, is a heterogeneous disease with variable clinical presentation and evolution 1,2 . Two major molecular subtypes can be distinguished, characterized respectively by a high or low number of somatic hypermutations in the variable region of immunoglobulin genes 3,4 . The molecular changes leading to the pathogenesis of the disease are still poorly understood. Here we performed whole-genome sequencing of four cases of CLL and identified 46 somatic mutations that potentially affect gene function. Further analysis of these mutations in 363 patients with CLL identified four genes that are recurrently mutated: notch 1 (NOTCH1), exportin 1 (XPO1), myeloid differentiation primary response gene 88 (MYD88) and kelch-like 6 (KLHL6). Mutations in MYD88 and KLHL6 are predominant in cases of CLL with mutated immunoglobulin genes, whereas NOTCH1 and XPO1 mutations are mainly detected in patients with unmutated immunoglobulins. The patterns of somatic mutation, supported by functional and clinical analyses, strongly indicate that the recurrent NOTCH1, MYD88 and XPO1 mutations are oncogenic changes that contribute to the clinical evolution of the disease. To our knowledge, this is the first comprehensive analysis of CLL combining whole-genome sequencing with clinical characteristics and clinical outcomes. It highlights the usefulness of this approach for the identification of clinically relevant mutations in cancer.To gain insights into the molecular alterations that cause CLL, we performed whole-genome sequencing of four cases representative of different forms of the disease: two cases, CLL1 and CLL2, with no mutations in the immunoglobulin genes (IGHV-unmutated) and two cases, CLL3 and CLL4, with mutations in these genes (IGHV-mutated) (Supplementary Table 1 and Supplementary Information). We used a combination of whole-genome sequencing and exome sequencing, as well as long-insert paired-end libraries, to detect variants in chromosomal structure (Supplementary Fig. 1 and Supplementary Tables 2-5). We obtained more than 99.7% concordance between whole-genome sequencing calls and genotyping data, indicating that the coverage and parameters used were sufficient to detect most of the sequence variants in these samples (Supplementary Information). We detected about 1,000 somatic mutations per tumour in non-repetitive regions (Fig. 1a, Supplementary Fig. 2 and Supplementary Table 6). These numbers of somatic mutations were lower than the numbers in melanoma and lung carcinoma 5,6 , but in agreement with previous estimates of less than one mutation per megabase (Mb) for leukaemias 7 . The most common substitution was the transition G>A/C>T, usually occurring in a CpG context (Fig. 1b and Supplementary Fig. 2). We also detected marked differences in the mutation pattern between CLL samples and these differences were associated with tumour subtype (Fig. 1b). Thus, IGHV-mutated cases showed a higher proportion of A>C/T>G mutations tha...
Chronic lymphocytic leukaemia (CLL) is a frequent disease in which the genetic alterations determining the clinicobiological behaviour are not fully understood. Here we describe a comprehensive evaluation of the genomic landscape of 452 CLL cases and 54 patients with monoclonal B-lymphocytosis, a precursor disorder. We extend the number of CLL driver alterations, including changes in ZNF292, ZMYM3, ARID1A and PTPN11. We also identify novel recurrent mutations in non-coding regions, including the 3' region of NOTCH1, which cause aberrant splicing events, increase NOTCH1 activity and result in a more aggressive disease. In addition, mutations in an enhancer located on chromosome 9p13 result in reduced expression of the B-cell-specific transcription factor PAX5. The accumulative number of driver alterations (0 to ≥4) discriminated between patients with differences in clinical behaviour. This study provides an integrated portrait of the CLL genomic landscape, identifies new recurrent driver mutations of the disease, and suggests clinical interventions that may improve the management of this neoplasia.
Here we perform whole-exome sequencing of samples from 105 individuals with chronic lymphocytic leukemia (CLL), the most frequent leukemia in adults in Western countries. We found 1,246 somatic mutations potentially affecting gene function and identified 78 genes with predicted functional alterations in more than one tumor sample. Among these genes, SF3B1, encoding a subunit of the spliceosomal U2 small nuclear ribonucleoprotein (snRNP), is somatically mutated in 9.7% of affected individuals. Further analysis in 279 individuals with CLL showed that SF3B1 mutations were associated with faster disease progression and poor overall survival. This work provides the first comprehensive catalog of somatic mutations in CLL with relevant clinical correlates and defines a large set of new genes that may drive the development of this common form of leukemia. The results reinforce the idea that targeting several well-known genetic pathways, including mRNA splicing, could be useful in the treatment of CLL and other malignancies.
Human aging cannot be fully understood in terms of the constrained genetic setting. Epigenetic drift is an alternative means of explaining age-associated alterations. To address this issue, we performed whole-genome bisulfite sequencing (WGBS) of newborn and centenarian genomes. The centenarian DNA had a lower DNA methylation content and a reduced correlation in the methylation status of neighboring cytosine-phosphate-guanine (CpGs) throughout the genome in comparison with the more homogeneously methylated newborn DNA. The more hypomethylated CpGs observed in the centenarian DNA compared with the neonate covered all genomic compartments, such as promoters, exonic, intronic, and intergenic regions. For regulatory regions, the most hypomethylated sequences in the centenarian DNA were present mainly at CpG-poor promoters and in tissue-specific genes, whereas a greater level of DNA methylation was observed in CpG island promoters. We extended the study to a larger cohort of newborn and nonagenarian samples using a 450,000 CpG-site DNA methylation microarray that reinforced the observation of more hypomethylated DNA sequences in the advanced age group. WGBS and 450,000 analyses of middle-age individuals demonstrated DNA methylomes in the crossroad between the newborn and the nonagenarian/centenarian groups. Our study constitutes a unique DNA methylation analysis of the extreme points of human life at a single-nucleotide resolution level.epigenomics | longevity D uring human aging, progressive impairment of organ and tissue functionality leads to an increasing probability of death. The molecular culprits behind this decline in physiological activities remain largely unknown. Studies of transcriptional and genomic associations in distinct tissues have identified several gene families and cellular pathways that might contribute to aging and alter lifespan. These families include the Sirtuins, DNA repair enzymes, insulin-signaling pathway/forkhead transcription factors, apolipoproteins, telomere biology, and oxidative damage/ mitochondrial metabolism (1, 2). Aging-associated mechanisms apparently involve many networks within a given cell. Considering that epigenetic regulation has emerged as a critical driver of cell fate and survival that targets many pathways (3, 4), that epigenetic drift can occur even in genetically identical humans (5, 6), and that DNA methylation patterns are disrupted in a wide range of common human diseases (7-11), we wondered whether individuals at the most extreme points of their lifespan had different DNA methylomes. To address this issue, we used whole-genome bisulfite sequencing (WGBS) (12-16) and a 450,000 CpG DNA methylation microarray to examine the DNA methylation profiles of newborn and nonagenarian/centenarian samples.Results and Discussion WGBS of Newborn and Centenarian DNA. The initial data were generated from the cord blood of a newborn (male Caucasian; NB) and from a centenarian (103-y-old male Caucasian; Y103) using DNA extracted from CD4 + T cells processed through an Illumina G...
We have extensively characterized the DNA methylomes of 139 patients with chronic lymphocytic leukemia (CLL) with mutated or unmutated IGHV and of several mature B-cell subpopulations through the use of whole-genome bisulfite sequencing and high-density microarrays. The two molecular subtypes of CLL have differing DNA methylomes that seem to represent epigenetic imprints from distinct normal B-cell subpopulations. DNA hypomethylation in the gene body, targeting mostly enhancer sites, was the most frequent difference between naive and memory B cells and between the two molecular subtypes of CLL and normal B cells. Although DNA methylation and gene expression were poorly correlated, we identified gene-body CpG dinucleotides whose methylation was positively or negatively associated with expression. We have also recognized a DNA methylation signature that distinguishes new clinico-biological subtypes of CLL. We propose an epigenomic scenario in which differential methylation in the gene body may have functional and clinical implications in leukemogenesis.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.