We conducted a genome-wide association study of 299,983 tagging SNPs for chronic lymphocytic leukemia (CLL) and performed validation in two additional series totaling 1,529 cases and 3,115 controls. We identified six previously unreported CLL risk loci at 2q13 (rs17483466; P = 2.36 x 10(-10)), 2q37.1 (rs13397985, SP140; P = 5.40 x 10(-10)), 6p25.3 (rs872071, IRF4; P = 1.91 x 10(-20)), 11q24.1 (rs735665; P = 3.78 x 10(-12)), 15q23 (rs7176508; P = 4.54 x 10(-12)) and 19q13.32 (rs11083846, PRKD2; P = 3.96 x 10(-9)). These data provide the first evidence for the existence of common, low-penetrance susceptibility to a hematological malignancy and new insights into disease causation in CLL.
To identify novel risk variants for chronic lymphocytic leukemia (CLL) we conducted a genome-wide association study of 299,983 tagging SNPs, with validation in four additional series totaling 2,503 cases and 5,789 controls. We identified four risk loci for CLL at 2q37.3 (rs757978, FARP2; odds ratio [OR] = 1.39; P = 2.11 x 10-9), 8q24.21 (rs2456449; OR = 1.26; P = 7.84 x 10-10), 15q21.3 (rs7169431; OR = 1.36; P = 4.74 x 10-7) and 16q24.1 (rs305061; OR = 1.22; P = 3.60 x 10-7). There was also evidence for risk loci at 15q25.2 (rs783540, CPEB1; OR = 1.18; P = 3.67 x 10-6) and 18q21.1 (rs1036935; OR = 1.22; P = 2.28 x 10-6). These data provide further evidence for genetic susceptibility to this B-cell hematological malignancy.
BackgroundThe histone variant histone H2A.X comprises up to 25% of the H2A complement in mammalian cells. It is rapidly phosphorylated following exposure of cells to double-strand break (DSB) inducing agents such as ionising radiation. Within minutes of DSB generation, H2AX molecules are phosphorylated in large chromatin domains flanking DNA double-strand breaks (DSBs); these domains can be observed by immunofluorescence microscopy and are termed γH2AX foci. H2AX phosphorylation is believed to have a role mounting an efficient cellular response to DNA damage. Theoretical considerations suggest an essentially random chromosomal distribution of X-ray induced DSBs, and experimental evidence does not consistently indicate otherwise. However, we observed an apparently uneven distribution of γH2AX foci following X-irradiation with regions of the nucleus devoid of foci.Methodology/Principle FindingsUsing immunofluorescence microscopy, we show that focal phosphorylation of histone H2AX occurs preferentially in euchromatic regions of the genome following X-irradiation. H2AX phosphorylation has also been demonstrated previously to occur at stalled replication forks induced by UV radiation or exposure to agents such as hydroxyurea. In this study, treatment of S-phase cells with hydroxyurea lead to efficient H2AX phosphorylation in both euchromatin and heterochromatin at times when these chromatin compartments were undergoing replication. This suggests a block to H2AX phosphorylation in heterochromatin that is at least partially relieved by ongoing DNA replication.Conclusions/SignificanceWe discus a number of possible mechanisms that could account for the observed pattern of H2AX phosphorylation. Since γH2AX is regarded as forming a platform for the recruitment or retention of other DNA repair and signaling molecules, these findings imply that the processing of DSBs in heterochromatin differs from that in euchromatic regions. The differential responses of heterochromatic and euchromatic compartments of the genome to DSBs will have implications for understanding the processes of DNA repair in relation to nuclear and chromatin organization.
) and 8q22.3 (rs2511714, P=2.90x10 -9 ). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CLL. Speedy et al 3Chronic lymphocytic leukemia (CLL) is the most common hematological malignancy in Western countries 1 and is characterized by a 8-fold increased risk in first-degree relatives 2 . Genome-wide association studies (GWASs) have so far identified common variants at 24 loci that contribute to the heritable risk of CLL [3][4][5][6] . Current projections for the number of independent regions harboring common variants associated with CLL suggest that additional risk loci conferring modest effects should be identified by expansion of discovery GWAS datasets.To identify additional novel susceptibility loci for CLL, we conducted an independent primary scan of CLL and performed a genome-wide meta-analysis with a previously published GWAS followed by analysis of the top single nucleotide polymorphisms (SNPs) in two separate case-control series.In the primary scan (UK-CLL-2), 1,271 CLL cases were genotyped using the Illumina Omni Express Figure 1). To harmonize the two GWAS datasets, we imputed UK-CLL-1 to recover untyped SNPs directly genotyped in UK-CLL-2, using data from the 1000 Genomes Project as reference. Using data on all cases and controls from each GWAS, we derived joint odds ratios (ORs) and confidence intervals (CIs) under a fixed effects model for each SNP and associated P-values, restricting analysis to SNPs with MAF >1%. After filtering on the basis of pre-specified quality-control measures Table 2). We also identified promising association signals (i.e. P<1.0×10−5 ) at 11 additional loci (Supplementary Table 2). We applied 1000 Genomes imputation to UK-CLL-1 and UK-CLL-2 at these loci to investigate if a statistically significant stronger SNP association could be identified, recovering an additional SNP which was significant at the genome-wide threshold (rs6858698; Supplementary Table 2). We performed replication genotyping of six SNPs selected on the basis of statistical significance (rs2236256, rs6062501, rs6858698) and gene centricity coupled with Table 4). While we found no evidence for a relationship between rs10936599, and telomere length in 246 CLL patients (Supplementary Table 5), carrier status for the rs10936599-C risk allele is previously been associated with significantly longer telomeres in leukocytes 10,11 .The third significant association was at rs6858698 on 4q26 (OR=1.31, 95% C.I. 1.20-1.44; P=3.07x10 linked to cis-platinum resistance by enhancing apoptosis. A recent GWAS of CLL has reported promising associations at 5p15.33 defined by rs10069690 and at 8q22.33 defined by rs2511714 6 . Combining the Pvalues for rs10069690 and rs2511714 obtained in our meta-analysis (P=1.0x10 -4 and 1.0x10respectively) with published data 6 provides robust evidence for both associations (combined P-values 1.10x10 -10 and 2.90x10 -9 respectively; Supplementary Figure 4). rs10069690 maps to intron 4 of TERT (telomerase reverse trans...
Several chronic lymphocytic leukaemia (CLL) susceptibility loci have been reported; however, much of the heritable risk remains unidentified. Here we perform a meta-analysis of six genome-wide association studies, imputed using a merged reference panel of 1,000 Genomes and UK10K data, totalling 6,200 cases and 17,598 controls after replication. We identify nine risk loci at 1p36.11 (rs34676223, P=5.04 × 10-13), 1q42.13 (rs41271473, P=1.06 × 10-10), 4q24 (rs71597109, P=1.37 × 10 -10), 4q35.1 (rs57214277, P=3.69 × 10-8), 6p21.31 (rs3800461, P=1.97 × 10-8), 11q23.2 (rs61904987, P=2.64 × 10-11), 18q21.1 (rs1036935, P=3.27 × 10-8), 19p13.3 (rs7254272, P=4.67 × 10-8) and 22q13.33 (rs140522, P=2.70 × 10-9). These new and established risk loci map to areas of active chromatin and show an over-representation of transcription factor binding for the key determinants of B-cell development and immune response
Despite huge improvements in the treatment of leukemia, the percentage of patients suffering relapse still remains significant. Relapse most often results from a small number of leukemic stem cells (LSCs) within the bone marrow, which are able to self-renew, and therefore reestablish the full tumor. The marrow microenvironment contributes considerably in supporting the protection and development of leukemic cells. LSCs share specific niches with normal hematopoietic stem cells with the niche itself being composed of a variety of cell types, including mesenchymal stem/stromal cells, bone cells, immune cells, neuronal cells, and vascular cells. A hallmark of the hematopoietic niche is low oxygen partial pressure, indeed this hypoxia is necessary for the long-term maintenance of hematopoietic stem/progenitor cells. Hypoxia is a strong signal, principally maintained by members of the hypoxia-inducible factor (HIF) family. In solid tumors, it has been well established that hypoxia triggers intrinsic metabolic changes and microenvironmental modifications, such as the stimulation of angiogenesis, through activation of HIFs. As leukemia is not considered a “solid” tumor, the role of oxygen in the disease was presumed to be inconsequential and remained long overlooked. This view has now been revised since hypoxia has been shown to influence leukemic cell proliferation, differentiation, and resistance to chemotherapy. However, the role of HIF proteins remains controversial with HIFs being considered as either oncogenes or tumor suppressor genes, depending on the study and model. The purpose of this review is to highlight our knowledge of hypoxia and HIFs in leukemic development and therapeutic resistance and to discuss the recent hypoxia-based strategies proposed to eradicate leukemias.
B-cell malignancies (BCM) originate from the same cell of origin, but at different maturation stages and have distinct clinical phenotypes. Although genetic risk variants for individual BCMs have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. We explored genome-wide association studies of chronic lymphocytic leukaemia (CLL, N = 1,842), Hodgkin lymphoma (HL, N = 1,465) and multiple myeloma (MM, N = 3,790). We identified a novel pleiotropic risk locus at 3q22.2 (NCK1, rs11715604, P = 1.60 × 10 −9 ) with opposing effects between CLL (P = 1.97 × 10 −8 ) and HL (P = 3.31 × 10 −3 ). Eight established non-HLA risk loci showed pleiotropic associations. Within the HLA region, Ser37 + Phe37 in HLA-DRB1 (P = 1.84 × 10 −12 ) was associated with increased CLL and HL risk (P = 4.68 × 10 −12 ), and reduced MM risk (P = 1.12 × 10 −2 ), and Gly70 in HLA-DQB1 (P = 3.15 × 10 −10 ) showed opposing effects between CLL (P = 3.52 × 10 −3 ) and HL (P = 3.41 × 10 −9 ). By integrating eQTL, Hi-C and ChIP-seq data, we show that the pleiotropic risk loci are enriched for B-cell regulatory elements, as well as an over-representation of binding of key B-cell
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