41 research outputs found

    Erratum to: Genetic alterations of m6A regulators predict poorer survival in acute myeloid leukemia

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    Abstract Methylation of N6 adenosine (m6A) is known to be important for diverse biological processes including gene expression control, translation of protein, and messenger RNA (mRNA) splicing. However, its role in the development of human cancers is poorly understood. By analyzing datasets from the Cancer Genome Atlas Research Network (TCGA) acute myeloid leukemia (AML) study, we discover that mutations and/or copy number variations of m6A regulatory genes are strongly associated with the presence of TP53 mutations in AML patients. Further, our analyses reveal that alterations in m6A regulatory genes confer a worse survival in AML. Our work indicates that genetic alterations of m6A regulatory genes may cooperate with TP53 and/or its regulator/downstream targets in the pathogenesis and/or maintenance of AML

    Lynch Syndrome Associated with Two MLH1 Promoter Variants and Allelic Imbalance of MLH1 Expression

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    © 2015 The Authors. **Human Mutation published by Wiley Periodicals, Inc. Lynch syndrome is a hereditary cancer syndrome caused by a constitutional mutation in one of the mismatch repair genes. The implementation of predictive testing and targeted preventative surveillance is hindered by the frequent finding of sequence variants of uncertain significance in these genes. We aimed to determine the pathogenicity of previously reported variants (c.-28A > G and c.-7C > T) within the MLH1 5â²untranslated region (UTR) in two individuals from unrelated suspected Lynch syndrome families. We investigated whether these variants were associated with other pathogenic alterations using targeted high-throughput sequencing of the MLH1 locus. We also determined their relationship to gene expr ession and epigenetic alterations at the promoter. Sequencing revealed that the c.-28A > G and c.-7C > T variants were the only potentially pathogenic alterations within the MLH1 gene. In both individuals, the levels of transcription from the variant allele were reduced to 50% compared with the wild-type allele. Partial loss of expression occurred in the absence of constitutional epigenetic alterations within the MLH1 promoter. We propose that these variants may be pathogenic due to constitutional partial loss of MLH1 expression, and that this may be associated with intermediate penetrance of a Lynch syndrome phenotype. Our findings provide further evidence of the potential importance of noncoding variants in the MLH1 5â²UTR in the pathogenesis of Lynch syndrome.Link_to_subscribed_fulltex

    Macrophage development and activation involve coordinated intron retention in key inflammatory regulators

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    Monocytes and macrophages are essential components of the innate immune system. Herein, we report that intron retention (IR) plays an important role in the development and function of these cells. Using Illumina mRNA sequencing, Nanopore direct cDNA sequencing and proteomics analysis, we identify IR events that affect the expression of key genes/proteins involved in macrophage development and function. We demonstrate that decreased IR in nuclear-detained mRNA is coupled with increased expression of genes encoding regulators of macrophage transcription, phagocytosis and inflammatory signalling, including ID2, IRF7, ENG and LAT. We further show that this dynamic IR program persists during the polarisation of resting macrophages into activated macrophages. In the presence of proinflammatory stimuli, intron-retaining CXCL2 and NFKBIZ transcripts are rapidly spliced, enabling timely expression of these key inflammatory regulators by macrophages. Our study provides novel insights into the molecular factors controlling vital regulators of the innate immune response

    Putative tumour-suppressor gene DAB2 is frequently down regulated by promoter hypermethylation in nasopharyngeal carcinoma

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    <p>Abstract</p> <p>Background</p> <p>Human Disabled-2 (DAB2), is a multi-function signalling molecule that it is frequently down-regulated in human cancers. We aimed to investigate the possible tumour suppressor effect of DAB2 in nasopharyngeal carcinoma (NPC).</p> <p>Methods</p> <p>We studied the expression of DAB2 in NPC cell lines, xenografts and primary tumour samples. The status of promoter methylation was assessed by methylation specific PCR and bisulfite sequencing. The functional role of DAB2 in NPC was investigated by re-introducing DAB2 expression into NPC cell line C666-1.</p> <p>Results</p> <p>Decrease or absent of <it>DAB2 </it>transcript was observed in NPC cell lines and xenografts. Loss of DAB2 protein expression was seen in 72% (33/46) of primary NPC as demonstrated by immunohistochemistry. Aberrant <it>DAB2 </it>promoter methylation was detected in 65.2% (30/46) of primary NPC samples by methylation specific PCR. Treatment of the DAB2 negative NPC cell line C666-1 with 5-aza-2'-deoxycytidine resulted in restoration of DAB2 expression in a dose-dependent manner. Overexpression of DAB2 in NPC cell line C666-1 resulted in reduced growth rate and 35% reduction in anchorage-dependent colony formation, and inhibition of serum-induced c-Fos expression compared to vector-transfected controls. Over expression of DAB2 resulted in alterations of multiple pathways as demonstrated by expression profiling and functional network analysis, which confirmed the role of DAB2 as an adaptor molecule involved in multiple receptor-mediated signalling pathways.</p> <p>Conclusions</p> <p>We report the frequent down regulation of DAB2 in NPC and the promoter hypermethylation contributes to the loss of expression of DAB2. This is the first study demonstrating frequent DAB2 promoter hypermethylation in human cancer. Our functional studies support the putative tumour suppressor effect of DAB2 in NPC cells.</p

    Use of anticoagulants and antiplatelet agents in stable outpatients with coronary artery disease and atrial fibrillation. International CLARIFY registry

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    The role and molecular characteristics of constitutional MLH1 epimutation in young-onset cancer.

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    Lynch syndrome, the commonest form of familial young-onset cancer, is typically caused by germline sequence mutations within the DNA mismatch repair genes, usually MLH1 or MSH2. Constitutional MLH1 epimutation, characterised by monoallelic promoter methylation and transcriptional silencing throughout normal somatic tissues, is an alternative cause of cancer predisposition in mutation-negative cases.This study aimed to further define the role of MLH1 epimutations in cancer causation and their molecular basis. Mutation-negative Lynch syndrome cases with MLH1-deficient tumours were screened for constitutional epimutation and allelic expression imbalance (AEI) of MLH1 using new CpG and allele-quantification pyrosequencing assays. This led to the identification of a novel intronic splice mutation in one patient demonstrating AEI, and new cases with an MLH1 epimutation. Loss-of-heterozygosity of the normal allele was demonstrated in their tumours. In one sporadic case, the epimutation arose de novo. The other cases were familial, and their epimutations demonstrated dominant inheritance linked to a particular ancestral founder genetic haplotype, indicative of a cis genetic-based defect. A single nucleotide variant within the 5'UTR, c.-27C>A, was investigated as the underlying cause. This epimutation was mosaic, as indicated by variable AEI among carriers. Furthermore, it was erased in spermatozoa and reset in the next generation.The molecular characteristics of constitutional MLH1 epimutations were examined in the cell lines from carriers to better characterise the epigenetic modifications associated with this defect. Allele-specific chromatin immunoprecipitation assays were developed at polymorphic sites within the MLH1 promoter to determine the histone profile associated with each allele. Elevated levels of repressive modifications were associated with the epimutant alleles, whereas the unmethylated alleles retained transcriptionally permissive moieties. Treatment with epigenetic reversal drugs partially up-regulated the epimutant alleles, indicating transcriptional activity is dependent on the presence of repressive chromatin modifications.This study provided evidence for two distinct forms of MLH1 epimutation associated with different inheritance patterns, reflecting different underlying mechanisms. A cis genetic alteration likely causes the dominant form, whereas trans-acting factors may be involved in non-Mendelian epimutations

    EXA-2017-1S-FARMACOLOGÍA Y NUTRICIÓN-1-1Par.pdf

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    Associations between shallow deletion and copy number gain of m6A regulatory genes and their mRNA expression in the TCGA AML cohort. Relative mRNA expression is displayed as Z-score, which indicates the number of standard deviation away from the mean expression of the reference population represented by non-mutated diploid samples. Mann-Whitney U test was used to determine significance. (PDF 395 kb

    Additional file 4: Table S2. of Genetic alterations of m6A regulators predict poorer survival in acute myeloid leukemia

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    Clinical and molecular characteristics of TCGA AML patients with a deletion or copy number loss of the gene encoding an m6A eraser, ALKBH5. (DOCX 92 kb

    Mosaic epigenetic inheritance as a cause of early-onset colorectal cancer

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    IMPORTANCE: Constitutional hypermethylation of 1 allele throughout the soma (constitutional epimutation) is an accepted mechanism of cancer predisposition. Understanding the origin and inheritance of epimutations is important for assessing cancer risk in affected families. OBSERVATIONS: We report a 29-year-old man with early-onset colorectal cancer who showed a constitutional MLH1 epimutation (approximately 50% of alleles methylated and allele-specific loss of MLH1 expression) that was stable over a 16-year period. The epimutation was inherited without a genetic alteration from his asymptomatic mother. She showed methylation on the same allele but in less than 5% of her somatic cells. CONCLUSIONS AND RELEVANCE: These findings indicate that low-level somatic mosaicism for an epimutation in an asymptomatic parent can produce a nonmosaic constitutional epimutation in a child. Asymptomatic low-level methylation in some individuals may be associated with substantial cancer risk to their offspring
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