scholarly journals MutationalPatterns: comprehensive genome-wide analysis of mutational processes

2016 ◽  
Author(s):  
Francis Blokzijl ◽  
Roel Janssen ◽  
Ruben van Boxtel ◽  
Edwin Cuppen
Keyword(s):  
Base Substitution ◽  
Bioconductor Package ◽  
Sequence Context ◽  
Mutational Signatures ◽  
Genomic Features ◽  
Dna Repair Mechanisms ◽  
Genome Wide ◽  
Repair Mechanisms ◽  
Mutational Processes ◽  
Type Sequence

AbstractBase substitution catalogs represent historical records of mutational processes that have been active in a system. Such processes can be distinguished by typical characteristics, like mutation type, sequence context, transcriptional and replicative strand bias, and distribution throughout the genome. MutationalPatterns is an R/Bioconductor package that characterizes this broad range of mutational patterns and potential relations with (epi-)genomic features. Furthermore, it offers an efficient method to quantify the contribution of known mutational signatures. Such analyses can be used to determine whether certain DNA repair mechanisms are perturbed and to further characterize the processes underlying known mutational signatures.

scholarly journals RUNX1-ETO: Attacking the Epigenome for Genomic Instable Leukemia

2019 ◽  
Vol 20 (2) ◽  
pp. 350 ◽  
Author(s):  
Emiel van der Kouwe ◽  
Philipp Staber
Keyword(s):  
Fusion Protein ◽  
Target Genes ◽  
Underlying Mechanism ◽  
Current Data ◽  
Distal Enhancer ◽  
Dna Repair Mechanisms ◽  
Genome Wide ◽  
Wide Range ◽  
Repair Mechanisms ◽  
Comprehensive Picture

Oncogenic fusion protein RUNX1-ETO is the product of the t(8;21) translocation, responsible for the most common cytogenetic subtype of acute myeloid leukemia. RUNX1, a critical transcription factor in hematopoietic development, is fused with almost the entire ETO sequence with the ability to recruit a wide range of repressors. Past efforts in providing a comprehensive picture of the genome-wide localization and the target genes of RUNX1-ETO have been inconclusive in understanding the underlying mechanism by which it deregulates native RUNX1. In this review; we dissect the current data on the epigenetic impact of RUNX1 and RUNX1-ETO. Both share similarities however, in recent years, research focused on epigenetic factors to explain their differences. RUNX1-ETO impairs DNA repair mechanisms which compromises genomic stability and favors a mutator phenotype. Among an increasing pool of mutated factors, regulators of DNA methylation are frequently found in t(8;21) AML. Together with the alteration of both, histone markers and distal enhancer regulation, RUNX1-ETO might specifically disrupt normal chromatin structure. Epigenetic studies on the fusion protein uncovered new mechanisms contributing to leukemogenesis and hopefully will translate into clinical applications.

scholarly journals The Repertoire of Mutational Signatures in Human Cancer

2018 ◽  
Author(s):  
Ludmil B Alexandrov ◽  
Jaegil Kim ◽  
Nicholas J Haradhvala ◽  
Mi Ni Huang ◽  
Alvin WT Ng ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Human Cancer ◽  
Base Substitution ◽  
Mutational Signatures ◽  
Insertion And Deletion ◽  
Damage Repair ◽  
Cancer Genomes ◽  
Dataset Size ◽  
Dna Maintenance ◽  
Mutational Processes

ABSTRACTSomatic mutations in cancer genomes are caused by multiple mutational processes each of which generates a characteristic mutational signature. Using 84,729,690 somatic mutations from 4,645 whole cancer genome and 19,184 exome sequences encompassing most cancer types we characterised 49 single base substitution, 11 doublet base substitution, four clustered base substitution, and 17 small insertion and deletion mutational signatures. The substantial dataset size compared to previous analyses enabled discovery of new signatures, separation of overlapping signatures and decomposition of signatures into components that may represent associated, but distinct, DNA damage, repair and/or replication mechanisms. Estimation of the contribution of each signature to the mutational catalogues of individual cancer genomes revealed associations with exogenous and endogenous exposures and defective DNA maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes contributing to the development of human cancer including a comprehensive reference set of mutational signatures in human cancer.

scholarly journals Cellular Response against Oxidative Stress, a Novel Insight into Lupus Nephritis Pathogenesis

2021 ◽  
Vol 11 (8) ◽  
pp. 693
Author(s):  
Corina Daniela Ene ◽  
Simona Roxana Georgescu ◽  
Mircea Tampa ◽  
Clara Matei ◽  
Cristina Iulia Mitran ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lupus Nephritis ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
Control Group ◽  
Dna Repair Mechanisms ◽  
Glycation End Products ◽  
Repair Mechanisms ◽  
Low Levels ◽  
Defective Dna Repair

The interaction of reactive oxygen species (ROS) with lipids, proteins, nucleic acids and hydrocarbonates promotes acute and chronic tissue damage, mediates immunomodulation and triggers autoimmunity in systemic lupus erythematous (SLE) patients. The aim of the study was to determine the pathophysiological mechanisms of the oxidative stress-related damage and molecular mechanisms to counteract oxidative stimuli in lupus nephritis. Our study included 38 SLE patients with lupus nephritis (LN group), 44 SLE patients without renal impairment (non-LN group) and 40 healthy volunteers as control group. In the present paper, we evaluated serum lipid peroxidation, DNA oxidation, oxidized proteins, carbohydrate oxidation, and endogenous protective systems. We detected defective DNA repair mechanisms via 8-oxoguanine-DNA-glycosylase (OGG1), the reduced regulatory effect of soluble receptor for advanced glycation end products (sRAGE) in the activation of AGE-RAGE axis, low levels of thiols, disulphide bonds formation and high nitrotyrosination in lupus nephritis. All these data help us to identify more molecular mechanisms to counteract oxidative stress in LN that could permit a more precise assessment of disease prognosis, as well as developing new therapeutic targets.

scholarly journals DNA Damage Response in Multiple Myeloma: The Role of the Tumor Microenvironment

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 504
Author(s):  
Takayuki Saitoh ◽  
Tsukasa Oda
Keyword(s):  
Multiple Myeloma ◽  
Dna Damage ◽  
Dna Repair ◽  
Tumor Microenvironment ◽  
Dna Damage Response ◽  
Genetic Instability ◽  
Dna Repair Mechanisms ◽  
Damage Response ◽  
Repair Mechanisms

Multiple myeloma (MM) is an incurable plasma cell malignancy characterized by genomic instability. MM cells present various forms of genetic instability, including chromosomal instability, microsatellite instability, and base-pair alterations, as well as changes in chromosome number. The tumor microenvironment and an abnormal DNA repair function affect genetic instability in this disease. In addition, states of the tumor microenvironment itself, such as inflammation and hypoxia, influence the DNA damage response, which includes DNA repair mechanisms, cell cycle checkpoints, and apoptotic pathways. Unrepaired DNA damage in tumor cells has been shown to exacerbate genomic instability and aberrant features that enable MM progression and drug resistance. This review provides an overview of the DNA repair pathways, with a special focus on their function in MM, and discusses the role of the tumor microenvironment in governing DNA repair mechanisms.

scholarly journals Ancient Sturgeons Possess Effective DNA Repair Mechanisms: Influence of Model Genotoxicants on Embryo Development of Sterlet, Acipenser ruthenus

2020 ◽  
Vol 22 (1) ◽  
pp. 6
Author(s):  
Ievgeniia Gazo ◽  
Roman Franěk ◽  
Radek Šindelka ◽  
Ievgen Lebeda ◽  
Sahana Shivaramu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Dna Repair ◽  
Embryo Development ◽  
Hatching Rate ◽  
Embryo Survival ◽  
Dna Repair Mechanisms ◽  
Acipenser Ruthenus ◽  
Repair Mechanisms ◽  
Sterlet Acipenser Ruthenus

DNA damage caused by exogenous or endogenous factors is a common challenge for developing fish embryos. DNA damage repair (DDR) pathways help organisms minimize adverse effects of DNA alterations. In terms of DNA repair mechanisms, sturgeons represent a particularly interesting model due to their exceptional genome plasticity. Sterlet (Acipenser ruthenus) is a relatively small species of sturgeon. The goal of this study was to assess the sensitivity of sterlet embryos to model genotoxicants (camptothecin, etoposide, and benzo[a]pyrene), and to assess DDR responses. We assessed the effects of genotoxicants on embryo survival, hatching rate, DNA fragmentation, gene expression, and phosphorylation of H2AX and ATM kinase. Exposure of sterlet embryos to 1 µM benzo[a]pyrene induced low levels of DNA damage accompanied by ATM phosphorylation and xpc gene expression. Conversely, 20 µM etoposide exposure induced DNA damage without activation of known DDR pathways. Effects of 10 nM camptothecin on embryo development were stage-specific, with early stages, before gastrulation, being most sensitive. Overall, this study provides foundational information for future investigation of sterlet DDR pathways.

scholarly journals Lineage-defined leiomyosarcoma subtypes emerge years before diagnosis and determine patient survival

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Nathaniel D. Anderson ◽  
Yael Babichev ◽  
Fabio Fuligni ◽  
Federico Comitani ◽  
Mehdi Layeghifard ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Therapeutic Strategy ◽  
Genetic Factors ◽  
Phylogenetic Reconstruction ◽  
Mutational Signatures ◽  
Multiple Tumor ◽  
Dystrophin Expression ◽  
Genome Wide ◽  
Damage Response ◽  
Disease Site

AbstractLeiomyosarcomas (LMS) are genetically heterogeneous tumors differentiating along smooth muscle lines. Currently, LMS treatment is not informed by molecular subtyping and is associated with highly variable survival. While disease site continues to dictate clinical management, the contribution of genetic factors to LMS subtype, origins, and timing are unknown. Here we analyze 70 genomes and 130 transcriptomes of LMS, including multiple tumor regions and paired metastases. Molecular profiling highlight the very early origins of LMS. We uncover three specific subtypes of LMS that likely develop from distinct lineages of smooth muscle cells. Of these, dedifferentiated LMS with high immune infiltration and tumors primarily of gynecological origin harbor genomic dystrophin deletions and/or loss of dystrophin expression, acquire the highest burden of genomic mutation, and are associated with worse survival. Homologous recombination defects lead to genome-wide mutational signatures, and a corresponding sensitivity to PARP trappers and other DNA damage response inhibitors, suggesting a promising therapeutic strategy for LMS. Finally, by phylogenetic reconstruction, we present evidence that clones seeding lethal metastases arise decades prior to LMS diagnosis.

scholarly journals Distinct genomic features across cytolytic subgroups in skin melanoma

2021 ◽  
Author(s):  
Constantinos Roufas ◽  
Ilias Georgakopoulos-Soares ◽  
Apostolos Zaravinos
Keyword(s):  
Immune Checkpoint ◽  
Cytolytic Activity ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition ◽  
Skin Melanoma ◽  
Related Gene ◽  
Mutational Signatures ◽  
Genomic Features ◽  
Immune Related Gene ◽  
Gene Sets

Abstract Background Skin melanoma is a highly immunogenic cancer. The intratumoral immune cytolytic activity (CYT) reflects the ability of cytotoxic T and NK cells to eliminate cancer cells, and is associated with improved patient survival. Despite the enthusiastic clinical results seen in advanced-stage metastatic melanoma patients treated with immune checkpoint inhibitors, a subgroup of them will later relapse and develop acquired resistance. We questioned whether CYT associates with different genomic profiles and thus, patient outcome, in skin melanoma. Methods We explored the TCGA-SKCM dataset and stratified patients to distinct subgroups of cytolytic activity. The tumor immune contexture, somatic mutations and recurrent copy number aberrations were calculated using quanTIseq, MutSigCV and GISTIC2. Chromothriptic events were explored using CTLPScanner and cancer neoepitopes were predicted with antigen garnish. Each tumor's immunophenoscore was calculated using Immunophenogram. Mutational signatures and kataegis were explored using SigProfiler and compared to the known single or doublet base substitution signatures from COSMIC. Results Metastatic skin melanomas had significantly higher CYT levels compared to primary tumors. We assessed enrichment for immune-related gene sets within CYT-high tumors, whereas, CYT-low tumors were enriched for non-immune related gene sets. In addition, distinct mutational and neoantigen loads, primarily composed of C > T transitions, along with specific types of copy number aberrations, characterized each cytolytic subgroup. We found a broader pattern of chromothripsis across CYT-low tumors, where chromosomal regions harboring chromothriptic events, contained a higher number of cancer genes. SBS7a/b, SBS5 and SBS1 were the most prevalent mutational signatures across both cytolytic subgroups, but SBS1 differed significantly between them. SBS7a/b was mutually exclusive with SBS5 and SBS1 in both CYT subgroups. CYT-high patients had markedly higher immunophenoscore, suggesting that they should display a clinical benefit upon treatment with immune checkpoint inhibition therapy, compared to CYT-low patients. Conclusions Overall, our data highlight the existence of distinct genomic features across cytolytic subgroups in skin melanoma, which might affect the patients' relapse rate or their acquisition of resistance to immune checkpoint inhibition therapies.

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