scholarly journals Comprehensive analysis of clustered mutations in cancer reveals recurrent APOBEC3 mutagenesis of ecDNA

2021 ◽  
Author(s):  
Erik N Bergstrom ◽  
Jens-Christian Luebeck ◽  
Mia Petljak ◽  
Vineet Bafna ◽  
Paul S. Mischel ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Human Cancer ◽  
Cancer Genes ◽  
Base Substitutions ◽  
Cancer Genomes ◽  
Cancer Types ◽  
Mutational Processes ◽  
Comprehensive Characterization

Clustered somatic mutations are common in cancer genomes with prior analyses revealing several types of clustered single-base substitutions, including doublet- and multi-base substitutions, diffuse hypermutation termed omikli, and longer strand-coordinated events termed kataegis. Here, we provide a comprehensive characterization of clustered substitutions and clustered small insertions and deletions (indels) across 2,583 whole-genome sequenced cancers from 30 cancer types. While only 3.7% of substitutions and 0.9% of indels were found to be clustered, they contributed 8.4% and 6.9% of substitution and indel drivers, respectively. Multiple distinct mutational processes gave rise to clustered indels including signatures enriched in tobacco smokers and homologous-recombination deficient cancers. Doublet-base substitutions were caused by at least 12 mutational processes, while the majority of multi-base substitutions were generated by either tobacco smoking or exposure to ultraviolet light. Omikli events, previously attributed to the activity of APOBEC3 deaminases, accounted for a large proportion of clustered substitutions. However, only 16.2% of omikli matched APOBEC3 patterns with experimental validation confirming additional mutational processes giving rise to omikli. Kataegis was generated by multiple mutational processes with 76.1% of all kataegic events exhibiting AID/APOBEC3-associated mutational patterns. Co-occurrence of APOBEC3 kataegis and extrachromosomal-DNA (ecDNA) was observed in 31% of samples with ecDNA. Multiple distinct APOBEC3 kataegic events were observed on most mutated ecDNA. ecDNA containing known cancer genes exhibited both positive selection and kataegic hypermutation. Our results reveal the diversity of clustered mutational processes in human cancer and the role of APOBEC3 in recurrently mutating and fueling the evolution of ecDNA.

scholarly journals Important role of indels in somatic mutations of human cancer genes

2010 ◽  
Vol 11 (1) ◽  
Author(s):  
Haiwang Yang ◽  
Yan Zhong ◽  
Cheng Peng ◽  
Jian-Qun Chen ◽  
Dacheng Tian
Keyword(s):  
Somatic Mutations ◽  
Human Cancer ◽  
Cancer Genes

scholarly journals Process-specific somatic mutation distributions vary with three-dimensional genome structure

2018 ◽  
Author(s):  
Kadir C. Akdemir ◽  
Victoria T. Le ◽  
Sarah Killcoyne ◽  
Devin A. King ◽  
Ya-Ping Li ◽  
...  
Keyword(s):  
Somatic Mutation ◽  
X Chromosome ◽  
Genome Organization ◽  
Somatic Mutations ◽  
Light Exposure ◽  
Human Cancer ◽  
Three Dimensional ◽  
Cancer Evolution ◽  
Cancer Types ◽  
Mutational Processes

AbstractSomatic mutations arise during the life history of a cell. Mutations occurring in cancer driver genes may ultimately lead to the development of clinically detectable disease. Nascent cancer lineages continue to acquire somatic mutations throughout the neoplastic process and during cancer evolution (Martincorena and Campbell, 2015). Extrinsic and endogenous mutagenic factors contribute to the accumulation of these somatic mutations (Zhang and Pellman, 2015). Understanding the underlying factors generating somatic mutations is crucial for developing potential preventive, therapeutic and clinical decisions. Earlier studies have revealed that DNA replication timing (Stamatoyannopoulos et al., 2009) and chromatin modifications (Schuster-Böckler and Lehner, 2012) are associated with variations in mutational density. What is unclear from these early studies, however, is whether all extrinsic and exogenous factors that drive somatic mutational processes share a similar relationship with chromatin state and structure. In order to understand the interplay between spatial genome organization and specific individual mutational processes, we report here a study of 3000 tumor-normal pair whole genome datasets from more than 40 different human cancer types. Our analyses revealed that different mutational processes lead to distinct somatic mutation distributions between chromatin folding domains. APOBEC- or MSI-related mutations are enriched in transcriptionally-active domains while mutations occurring due to tobacco-smoke, ultraviolet (UV) light exposure or a signature of unknown aetiology (signature 17) enrich predominantly in transcriptionally-inactive domains. Active mutational processes dictate the mutation distributions in cancer genomes, and we show that mutational distributions shift during cancer evolution upon mutational processes switch. Moreover, a dramatic instance of extreme chromatin structure in humans, that of the unique folding pattern of the inactive X-chromosome leads to distinct somatic mutation distribution on X chromosome in females compared to males in various cancer types. Overall, the interplay between three-dimensional genome organization and active mutational processes has a substantial influence on the large-scale mutation rate variations observed in human cancer.

scholarly journals Chromatin accessibility of primary human cancers ties regional mutational processes with tissues of origin

2021 ◽  
Author(s):  
Oliver Ocsenas ◽  
Jüri Reimand
Keyword(s):  
Human Cancer ◽  
Replication Timing ◽  
Chromatin Accessibility ◽  
Cancer Genes ◽  
Cancer Evolution ◽  
Normal Cells ◽  
Cancer Genomes ◽  
Localized Mutagenesis ◽  
Passenger Mutations ◽  
Mutational Processes

Regional mutagenesis in cancer genomes associates with DNA replication timing (RT) and chromatin accessibility (CA) of normal cells, however human cancer epigenomes remain uncharacterized in this context. Here we model megabase-scale mutation frequencies in 2517 cancer genomes with 773 CA and RT profiles of cancers and normal cells. We find that CA profiles of matching cancers, rather than normal cells, predict regional mutagenesis and mutational signatures, indicating that most passenger mutations follow the epigenetic landscapes of transformed cells. Carcinogen-induced and unannotated signatures show the strongest associations with epigenomes. Associations with normal cells in melanomas, lymphomas and SBS1 signatures suggest earlier occurrence of mutations in cancer evolution. Frequently mutated regions unexplained by CA and RT are enriched in cancer genes and developmental pathways, reflecting contributions of localized mutagenesis and positive selection. These results underline the complex interplay of mutational processes, genome function and evolution in cancer and tissues of origin.

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.

Long noncoding RNA ANRIL as a novel biomarker in human cancer

2020 ◽  
Vol 16 (35) ◽  
pp. 2981-2995
Author(s):  
Ning Lou ◽  
Guohong Liu ◽  
Yunbao Pan
Keyword(s):  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Cell Cycle Progression ◽  
Potential Role ◽  
Human Cancer ◽  
Cycle Progression ◽  
Diagnosis And Prognosis ◽  
Cancer Types ◽  
Cancer Medicine

The long noncoding RNA ANRIL, located in the human chromosome 9p21 region, has been reported to be involved in tumor progression. ANRIL regulates gene expression via recruiting PRC2 or titrating miRNA; it also participates in signaling pathways. Evidence has indicated that ANRIL is overexpressed in many cancer types and is capable of enhancing cell proliferation and cell cycle progression and inhibiting apoptosis and senescence. ANRIL has the potential to serve as a biomarker for diagnosis and prognosis in cancer. In this article we focus on recent advances in studies of the oncogenic role of ANRIL and its potential role in cancer medicine.

scholarly journals Heat Shock Proteins Are Essential Components in Transformation and Tumor Progression: Cancer Cell Intrinsic Pathways and Beyond

2019 ◽  
Vol 20 (18) ◽  
pp. 4507 ◽  
Author(s):  
Lang ◽  
Guerrero-Giménez ◽  
Prince ◽  
Ackerman ◽  
Bonorino ◽  
...  
Keyword(s):  
Heat Shock ◽  
Cancer Cells ◽  
Stress Proteins ◽  
De Novo ◽  
Human Cancer ◽  
Essential Components ◽  
Wide Range ◽  
Cancer Types ◽  
Shock Proteins

Heat shock protein (HSP) synthesis is switched on in a remarkably wide range of tumor cells, in both experimental animal systems and in human cancer, in which these proteins accumulate in high levels. In each case, elevated HSP concentrations bode ill for the patient, and are associated with a poor outlook in terms of survival in most cancer types. The significance of elevated HSPs is underpinned by their essential roles in mediating tumor cell intrinsic traits such as unscheduled cell division, escape from programmed cell death and senescence, de novo angiogenesis, and increased invasion and metastasis. An increased HSP expression thus seems essential for tumorigenesis. Perhaps of equal significance is the pronounced interplay between cancer cells and the tumor milieu, with essential roles for intracellular HSPs in the properties of the stromal cells, and their roles in programming malignant cells and in the release of HSPs from cancer cells to influence the behavior of the adjacent tumor and infiltrating the normal cells. These findings of a triple role for elevated HSP expression in tumorigenesis strongly support the targeting of HSPs in cancer, especially given the role of such stress proteins in resistance to conventional therapies.

Comprehensive characterization of the rRNA metabolism-related genes in human cancer

Oncogene ◽  
2019 ◽  
Vol 39 (4) ◽  
pp. 786-800 ◽  
Author(s):  
Kaisa Cui ◽  
Cheng Liu ◽  
Xu Li ◽  
Qiang Zhang ◽  
Youjun Li
Keyword(s):  
Human Cancer ◽  
Comprehensive Characterization

scholarly journals Conceptualizing consumption in the imagination

2017 ◽  
Vol 18 (3) ◽  
pp. 327-347 ◽  
Author(s):  
Rebecca Jenkins ◽  
Mike Molesworth
Keyword(s):  
Consumer Research ◽  
Macro Level ◽  
Market Structures ◽  
Level Of Abstraction ◽  
Temporal Location ◽  
Individual Consumption ◽  
Presence And Absence ◽  
Comprehensive Characterization

In this article we extend theory relating to the imagination and markets by reviewing explicit and implicit work in marketing, consumer research and sociology, drawing on a broader literature that provides a more comprehensive characterization of imagining. We map consumption in the imagination in order to better define the concept and to differentiate forms of imagining according to a number of characteristics that are identified in the literature. These are as follows: (1) temporal location, (2) range of emotions, (3) degree of elaboration, (4) level of abstraction (5) purpose, and (6) prompts. We also consider the role of consumption in terms of its level of presence and absence in the imagination. We then present a trajectory of consumption in the imagination that seeks to account for the relationships and movements between forms of imagining and the marketplace, noting the importance of the imagination in terms of implications for macro-level market structures and individual consumption practice.

The landscape of somatic mutation in normal colorectal epithelial cells

2018 ◽  
Author(s):  
Henry Lee-Six ◽  
Peter Ellis ◽  
Robert J. Osborne ◽  
Mathijs A. Sanders ◽  
Luiza Moore ◽  
...  
Keyword(s):  
Normal Tissue ◽  
Somatic Mutations ◽  
Cell Lineage ◽  
Driver Mutations ◽  
Normal Cells ◽  
Genetic Changes ◽  
Adult Cell ◽  
Neoplastic Change ◽  
Cancer Types ◽  
Mutational Processes

AbstractThe colorectal adenoma-carcinoma sequence has provided a paradigmatic framework for understanding the successive somatic genetic changes and consequent clonal expansions leading to cancer. As for most cancer types, however, understanding of the earliest phases of colorectal neoplastic change, which may occur in morphologically normal tissue, is comparatively limited because of the difficulty of detecting somatic mutations in normal cells. Each colorectal crypt is a small clone of cells derived from a single recently-existing stem cell. Here, we whole genome sequenced hundreds of normal crypts from 42 individuals. Signatures of multiple mutational processes were revealed, some ubiquitous and continuous, others only found in some individuals, in some crypts or during some phases of the cell lineage from zygote to adult cell. Likely driver mutations were present in ∼1% of normal colorectal crypts in middle-aged individuals, indicating that adenomas and carcinomas are rare outcomes of a pervasive process of neoplastic change across morphologically normal colorectal epithelium.

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