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Chromosomal ideogram representing the different gene affected by recurrent non-coding mutations according to LARVA.
Source publication
Mutations in non-coding DNA regions are increasingly recognized as cancer drivers. These mutations can modify gene expression in cis or by inducing high-order chormatin structure modifications with long-range effects. Previous analysis reported the detection of recurrent and functional non-coding DNA mutations in the chronic lymphocytic leukemia (C...
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... relevant inflation in p-value distribution was observed. (Supplementary Fig. 1). These regions were located in 44 different genomic loci (Fig. 1). ...
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... enriched in mutations. LARVA detected significant mutation enrichments (q-value < 0.05) in 120 TFBS, 16 DHS regions, 10 enhancers, 4 promoters, 2 5′UTRs and 1 lincRNA (Table 1, Supplementary Tables 1-6). No relevant inflation in p-value distribution was observed. (Supplementary Fig. 1). These regions were located in 44 different genomic loci (Fig. 1). The most recurrently mutated promoters were those of TCL1A (q-value 3.32 × 10 −4 ), LCN6 (q-value 4.17 × 10 −3 ), ZFP36L1 (q-value 3.25 × 10 −2 ) and WDR97 (q-value 0.04); and the most significantly mutated enhancers were GH01J229147 (intergenic region chr1:229283343-229284982, q-value 5.79 × 10 −6 ) and GH07J000467 (PDGFA gene, ...
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... significant enhancer regions were located in the proximity of genes involved in apoptosis (BCL2 and BIRC3), cell cycle control (WBP2NL), cytoskeleton and extracellular matrix formation (ARPC3 and ITIH5), gene expression regulation and chromatin remodelling (BCL7A, PAX5 and PHF2), genome integrity (XRCC5 and ZNF506), gene expression regulation (MALAT1 and RBFOX3), intracellular signalling (DACT2, HIPK2, IMPA2, KCTD10, ROR2 and S1PR2), immune pathways (BACH2, LTB and MADCAM1) and metabolism (AKR1B15, AMPD3, GSTM1/GSTM2, LRP5 and ST6GAL1) ( Supplementary Tables 1-6). Recurrent mutations were also found near less well-characterized genes such as TMEM54 and CTBP2P5, as well as within intergenic regions such chr14:26068671-26069217 and chr1:229283491-229285693. ...
Citations
... Many B cell tumors also showed evidence of ectopic AID-induced somatic hypermutation [156][157][158][159]. Many of the hypermutated regions do not encode proteins but include altered regulatory sites that stimulate expression of putative oncogenic loci in DLBCL tumors [160,161]. It was known from work on immunoglobulin SHM that AID activity was targeted specifically to V region exons in the producing cells by special "diversity activation" (DIVAC) enhancer elements at each IG locus [162]. ...
Simple Summary
Cancer genomes can undergo major restructurings involving many chromosomal locations at key stages in tumor development. This restructuring process has been designated “genome chaos” by some authors. In order to examine how chaotic cancer genome restructuring may be, the cell and molecular processes for DNA restructuring are reviewed. Examination of the action of these processes in various cancers reveals a degree of specificity that indicates genome restructuring may be sufficiently reproducible to enable possible therapies that interrupt tumor progression to more lethal forms.
Abstract
Cancer genomes evolve in a punctuated manner during tumor evolution. Abrupt genome restructuring at key steps in this evolution has been called “genome chaos.” To answer whether widespread genome change is truly chaotic, this review (i) summarizes the limited number of cell and molecular systems that execute genome restructuring, (ii) describes the characteristic signatures of DNA changes that result from activity of those systems, and (iii) examines two cases where genome restructuring is determined to a significant degree by cell type or viral infection. The conclusion is that many restructured cancer genomes display sufficiently unchaotic signatures to identify the cellular systems responsible for major oncogenic transitions, thereby identifying possible targets for therapies to inhibit tumor progression to greater aggressiveness.
... 30 The Agilent SureSelect QXT Target Enrichment system for Illumina Multiplexed Sequencing (Agilent Tech-nologies, Santa Clara, CA) was used to produce libraries of exonic regions from 54 genes CLL-related as well as from BCL2, IGLL5 and NOTCH1 UTR regions (Supplementary Methods). Genes included in the custom-designed panel 31,32 are involved in CLL pathogenesis and the UTR regions were considered due to the previous identification of IGLL5, BCL2 and NOTCH1 UTRs somatic mutations in CLL 8,33,34 (Supplementary Table S2). Paired-end sequencing (151-bp reads) was run on the Illumina NextSeq instrument (Illumina, San Diego, CA). ...
Chromosome 14q32 rearrangements/translocations involving the immunoglobulin heavy chain (IGH) are rarely detected in chronic lymphocytic leukemia (CLL). The prognostic significance of the IGH translocation is controversial and its mutational profile remains unknown. Here, we present for the first time a comprehensive next‐generation sequencing (NGS) analysis of 46 CLL patients with IGH rearrangement (IGHR‐CLLs) and we demonstrate that IGHR‐CLLs have a distinct mutational profile with recurrent mutations in NOTCH1, IGLL5, POT1, BCL2, FBXW7, ZMYM3, MGA, BRAF and HIST1H1E genes. Interestingly, BCL2 and FBXW7 mutations were significantly associated with this subgroup and almost half of BCL2, IGLL5 and HISTH1E mutations reported were previously identified in non‐Hodgkin lymphomas. Notably, IGH/BCL2 rearrangements were associated with a lower mutation frequency and carried BCL2 and IGLL5 mutations, while the other IGHR‐CLLs had mutations in genes related to poor prognosis (NOTCH1, SF3B1 and TP53) and shorter time to first treatment (TFT). Moreover, IGHR‐CLLs patients showed a shorter TFT than CLL patients carrying 13q−, normal fluorescence in situ hybridization (FISH) and +12 CLL, being this prognosis particularly poor when NOTCH1, SF3B1, TP53, BIRC3 and BRAF were also mutated. The presence of these mutations not only was an independent risk factor within IGHR‐CLLs, but also refined the prognosis of low‐risk cytogenetic patients (13q−/normal FISH). Hence, our study demonstrates that IGHR‐CLLs have a distinct mutational profile from the majority of CLLs and highlights the relevance of incorporating NGS and the status of IGH by FISH analysis to refine the risk‐stratification CLL model.
Several intracellular pathological processes have been reported to be regulated by the FAM19A5/S1PR1 signaling pathway. However, the role of FAM19A5/S1PR1 signaling pathway in the viability and proliferation of mantle cell lymphoma is not been completely understood. The task of this study is to explore the influence of FAM19A5/S1PR1 signaling pathway in affecting the survival and growth of mantle cell lymphoma. shRNAs against FAM19A5 or S1PR1 were transfected into mantle cell lymphom. Cell viability and proliferation were measured through MTT assay and CCK8 assay, respectively. Our results demonstrated that loss of FAM19A5 significantly reduced the viability of mantle cell lymphom, an effect that was followed by a drop in cell proliferation capacity. Besides, inhibition of S1PR1 also impairs cell survival and interrupt mantle cell lymphom proliferation in vitro. Taken together, our results illustrate that FAM19A5/S1PR1 signaling pathway is associated with the regulation of mantle cell lymphom viability and proliferation. This finding will provide a potential target for the treatment of malignant lymphoma in the clinical practice.
Human pluripotent stem cells such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) provide unprecedented opportunities for cell therapies against intractable diseases and injuries. Both ESCs and iPSCs are already being used in clinical trials. However, we continue to encounter practical issues that limit their use, including their inherent properties of tumorigenicity, immunogenicity, and heterogeneity. Here, I review two decades of research aimed at overcoming these three difficulties.
