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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.
Familial hypercholesterolemia
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
Germ-line interruptions in the LDLR and APOBEC1 genes in mice provide a model for homozygous FH. Introduction of the gene for mouse LDLR with an adenovirus vector to the livers of LDLR(−/−)APOBEC1(−/−) mice led to an 87 percent regression of atherosclerotic lesions [92].
Endocrine and Metabolic Side Effects
Published in Ayse Serap Karadag, Berna Aksoy, Lawrence Charles Parish, Retinoids in Dermatology, 2019
Ayse Serap Karadag, Emin Ozlu, Bodo C. Melnik
Isotretinoin-mediated upregulation of p53 and FoxO1 may explain isotretinoin-induced hypertriglyceridemia. In studying human hepatocytes, ATRA activates the p14-MDM2-p53 pathway stabilizing p53 (128), which promotes the expression of FoxO1 (109). Each VLDL molecule contains one apoB-100, which is required for TG loading onto the VLDL particle. ApoB-100 and apoB-48 are created by a premature stop codon by apoB mRNA-editing enzyme complex 1 (apobec1). Notably, p53 response elements (p53RE) in the genes encoding for apoB and apobec1 have been detected. Both genes are transcriptionally regulated by p53 (129). Increased ATRA-p53 signaling may thus explain enhanced hepatic synthesis of VLDL apoB. Hepatic VLDL synthesis is also controlled by FoxO1. Augmented FoxO1 activity promotes hepatic VLDL overproduction and predisposes to the development of hypertriglyceridemia (130). TG loading to apoB-100 is facilitated by microsomal TG transfer protein (MTP), which is activated by FoxO1 (131,132).
Type I interferon detection in autoimmune diseases: challenges and clinical applications
Published in Expert Review of Clinical Immunology, 2021
Vassilis E. Papadopoulos, Charalampos Skarlis, Maria-Eleftheria Evangelopoulos, Clio P. Mavragani
Over the last decade, a growing body of evidence suggests that epigenetic mechanisms are associated to both autoimmunity and type I IFNs pathway activation. Aberrant DNA methylation–one of the major epigenetic mechanisms [86]– has been recently observed in several autoimmune diseases, including GD, RA, SLE and SSc suggesting that it could represent an important contributor in autoimmunity [86,87]. Moreover, hypomethylation of IFN-related genes has been observed in CD4+ cells derived from RA, GD, SLE, and SSc patients [88]. In line with this, hypomethylation of LINE1 and consecutively LINE1 transcript overexpression has been found in lupus kidney and SS MSG tissue compared to controls, positively correlating with IFNα and IFNβ expression, suggesting endogenous retroelements as potential triggers of type I IFNs [26]. The observed hypomethylation of LINE1 promoter, leading to inappropriate LINE1 overexpression, has been correlated to decreased lymphoid-specific helicase expression in both SS MSG and SLE kidney tissues, as well as lower DNMT3A and LINE1 expression in SLE kidney tissue and PBMCs [89]. Additionally, it was recently revealed that APOBEC3A –an mRNA editing enzyme– expression strongly correlates with both LINE1 and IFNα transcript levels in SS patients MSGs [90]. Given that the members of APOBEC family can act as LINE1 suppressors, these findings reflect a potentially compensatory role against endogenous retroelements [90].
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].
Age-related mutational signature negatively associated with immune activity and survival outcome in triple-negative breast cancer
Published in OncoImmunology, 2020
Hao Chen, Wei Chong, Xiaorong Yang, Yuan Zhang, Shaowei Sang, Xiangchun Li, Ming Lu
Recent advances have reported that genomic mutational signatures are associated with clinical prognosis and treatment response. Xing et al. revealed that mutational signature 18 was significantly enriched in tumors with cadherin 1 (CDH1) mutations and associated with poor prognoses in gastric cancer.34 There is evidence that the APOBEC mutational signature is a potential predictive marker for PD-1 immunotherapy response in NSCLC.13,35 In our genomic meta-analysis, we identified that signature 1 was associated with shortened survival time in patients with TNBC and suggested a significant association with tumor escape from immunological surveillance. A recent study indicated that short-term chemotherapy (e.g., doxorubicin and cisplatin) may induce a more favorable tumor microenvironment and increase the likelihood of response to PD-1 blockade in TNBC.36 Therefore, we speculated that patients with signature 1 after induction treatments of doxorubicin and cisplatin may improve the clinical benefit of immune checkpoint inhibitor therapy.