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Aberrant Methylation of UC Promoters in Human Pancreatic Ductal Carcinomas
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Michiyo Higashi, Seiya Yokoyama
Members of the Ten-Eleven Translocation (TET) family and/ or activation-induced deaminase (AID)/ APOBEC family were demethylated by conversion from 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further oxidized products in mammalian genomes (i.e. active DNA) [41, 42]. Thus, we evaluated differences in expression of DNA methylation-related enzymes in pancreatic neoplastic regions and non-neoplastic regions; MUC1 and MUC4 mRNA expression correlate with DNA methylation-related enzymes or MUC1 and MUC4 methylation status [43]. In general, neoplastic regions expressed lower levels of DNA demethylation factors (TET1, TET2) and DNA methylation factors (DNMT1) than non-neoplastic regions (p<0.001 in all three factors). Conversely, the neoplastic regions expressed more MUC4 and hypoxia biomarker (CAIX) than the non-neoplastic regions (p < 0.001 in both factors). This result suggested that neoplastic regions have altered regulation of epigenetic status. A multiple regression analysis revealed significant correlations for non-neoplastic samples between promoter hypomethylation status and the expression of enzymes related to DNA methylation. However, neoplastic samples showed no correlation between promoter hypomethylation status and expression of enzymes related to DNA methylation. These results suggest that epigenetic regulation of MUC1 and MUC4 by these enzymes was ineffective or altered in neoplastic regions.
Bladder Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Bladder cancer has a high mutation rate with TCGA reporting a median of 5.8 mutations per megabase. An analysis of mutation signatures suggested that around 67% of mutations were due to APOBEC mutagenesis. Other mutations were associated with 5-methylcytosine deamination, POLE, and ERCC2 mutations. Patients with a high mutation burden and APOBEC signature seemed to have better prognosis.
Gene Therapy for Cardiovascular Diseases
Published in Yashwant Pathak, Gene Delivery, 2022
Dhwani Thakkar, Vandit Shah, Jigna Shah
Atherosclerotic lesions gear up their formation in the second decade of life and proceed for the next 20 to 40 years as clinically important lesions. Pathogenesis of atherosclerosis involves several genes and environmental factors. Thus, atherosclerosis is not treated with the help of single gene or local gene transfer. In order to make the gene therapy a successful venture in atherosclerosis, many hereditary diseases and single gene defects that are susceptible to atherosclerosis need to be addressed. Here we discuss a few single gene transfers that facilitate to treat atherosclerosis. For example, lecithin cholesterol acetyl transferase (LCAT) or lipid transfer protein gene transfer can be used to treat certain dyslipoproteinemias. Gene transfer of very low density lipoprotein (VLDL) and low density lipoprotein (LDL) to the liver is an efficient treatment for low density lipoprotein receptor dysfunction.17, 18 Gene transfer of the catalytic subunit of the ApoB editing enzyme-apobec-1 can suppress elevated levels of atherogenic apolipoprotein (Apo) B100.19 Similarly, apoE gene transfer helps to decrease the lipoprotein levels that is used to treat type III hyperlipoproteinemia. In ApoA1 deficient patients, ApoA1 gene transfer is used to promote the reverse cholesterol transport. Patients with a lack of enzymes like hepatic lipase and lipoprotein lipase benefit from gene transfer since these enzymes are necessary for lipoprotein metabolism. Class A soluble scavengers and class B soluble scavenger receptors gene transfer also benefits by decreasing the lipid accumulation in macrophages and by altering high-density lipoprotein levels (HDL) respectively.
Next-generation sequencing for the diagnosis of hepatitis B: current status and future prospects
Published in Expert Review of Molecular Diagnostics, 2021
Selene Garcia-Garcia, Maria Francesca Cortese, Francisco Rodríguez-Algarra, David Tabernero, Ariadna Rando-Segura, Josep Quer, Maria Buti, Francisco Rodríguez-Frías
Several complex molecular mechanisms involving insertion/deletion events, as well as inter-genotype and intra-genotype recombination, further contribute to HBV genetic variability [29,30]. Host DNA and RNA deaminases can provide a powerful defense against viruses due to their mutagenic activity. However, they may cause further mutations in the viral genome, contributing to its complexity. In this regard, the apolipoprotein B mRNA editing enzyme catalytic polypeptide-like (APOBEC) induces massive cytidine to uridine (C-to-U) deamination on single-stranded nucleic acids (both DNA and RNA). This leads to G-to-A hypermutation on the HBV plus strand DNA, which can lead to cDNA instability and inhibition of viral replication [31,32]. However, some viral-edited genomes may resist degradation and be selected, leading to the occasional emergence of variants [33].
Deep sequencing as an approach to understanding the complexity and improving the treatment of multiple myeloma
Published in Expert Review of Precision Medicine and Drug Development, 2020
Louis S. Williams, Jessica Caro, Beatrice Razzo, Eileen M. Boyle, Gareth J. Morgan
The emergence of whole-genome sequencing allowed for accurate characterization signatures or ‘mutographs’ that reflects the mutational mechanisms underlying a particular event [58]. In order to better define mutational signatures in multiple myeloma, a landmark study in NDMM combined NGS with a non-negative matrix factorization algorithm to evaluate mutational signatures [37]. This investigation placed particular emphasis on MYC translocations and translocations involving the IGH locus for which there was adequate sequence information to define signatures [59]. This process identified a particular signature related to the apolipoprotein B editing complex (APOBEC) family of proteins. The signature, which is defined by C > T, C > G, and C > A substitutions in a TpC context, was enriched in patients harboring t(14;16) and t(14;20). These translocations overexpress MAF and MAFB, which are thought to regulate expression of the APOBEC proteins [60]. Kategis, a phenomenon associated with localized somatic hypermutation, was found to involve regions flanking translocations involving MYC and IGH loci [52,59,61]. This pattern has been attributed to the aberrant functioning of an adenosine deaminase (AID) that normally facilitates affinity maturation of germinal center B-cells [62].
Integrated analysis of the immunological and genetic status in and across cancer types: impact of mutational signatures beyond tumor mutational burden
Published in OncoImmunology, 2018
Jan Budczies, Anja Seidel, Petros Christopoulos, Volker Endris, Matthias Kloor, Balázs Győrffy, Barbara Seliger, Peter Schirmacher, Albrecht Stenzinger, Carsten Denkert
Of note, some mutational signatures showed stronger correlation with immune cell populations than TMB in specific cancer types. Particularly signatures characterized by C > T and C > G mutations at TpCpN trinucleotides most likely caused by DNA editing induced by cytidine deaminases of the APOBEC family44 showed high positive correlation with immunological variables compared to all mutational signatures and global mutation measures. These data are in line with reports showing that beyond their ability to directly act on viral genomes, APOBEC-induced deamination can positively modulate immunological response.45–47 The role of the two APOBEC-related MutSigs 2 and 13 was cancer type specific: For example, while we detected many significant associations with both MutSigs in BRCA, much stronger associations were detected for MutSig 2 compared to MutSig 13 in CESC. Similar observations were made for cancers harboring mutational signatures associated with DNA repair deficiency including MSI and POLE-mutations where specific immune cell compositions were associated with each of these deficient repair pathways in a cancer-type specific manner.