scholarly journals The effects of mutational processes and selection on driver mutations across cancer types

2017 ◽  
Author(s):  
Daniel Temko ◽  
Ian PM Tomlinson ◽  
Simone Severini ◽  
Benjamin Schuster-Böckler ◽  
Trevor A Graham
Keyword(s):  
Driver Mutations ◽  
Sequencing Data ◽  
Epidemiological Evidence ◽  
Dna Mismatch ◽  
Cancer Types ◽  
Key Driver ◽  
Independent Effects ◽  
Mutational Processes ◽  
Mutation And Selection

ABSTRACTEpidemiological evidence has long associated environmental mutagens with increased cancer risk. However, links between specific mutation-causing processes and the acquisition of individual driver mutations have remained obscure. Here we have used public cancer sequencing data to infer the independent effects of mutation and selection on driver mutation complement. First, we detect associations between a range of mutational processes, including those linked to smoking, ageing, APOBEC and DNA mismatch repair (MMR) and the presence of key driver mutations across cancer types. Second, we quantify differential selection between well-known alternative driver mutations, including differences in selection between distinct mutant residues in the same gene. These results show that while mutational processes play a large role in determining which driver mutations are present in a cancer, the role of selection frequently dominates.

scholarly journals Histone Modifying Enzymes in Gynaecological Cancers

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 816
Author(s):  
Priya Ramarao-Milne ◽  
Olga Kondrashova ◽  
Sinead Barry ◽  
John D. Hooper ◽  
Jason S. Lee ◽  
...  
Keyword(s):  
Genome Instability ◽  
Cpg Islands ◽  
Gene Promoter ◽  
Driver Mutations ◽  
Promoter Regions ◽  
Post Translational Modifications ◽  
Chromatin Dynamics ◽  
Cancer Types ◽  
Histone Modifying Enzymes

Genetic and epigenetic factors contribute to the development of cancer. Epigenetic dysregulation is common in gynaecological cancers and includes altered methylation at CpG islands in gene promoter regions, global demethylation that leads to genome instability and histone modifications. Histones are a major determinant of chromosomal conformation and stability, and unlike DNA methylation, which is generally associated with gene silencing, are amenable to post-translational modifications that induce facultative chromatin regions, or condensed transcriptionally silent regions that decondense resulting in global alteration of gene expression. In comparison, other components, crucial to the manipulation of chromatin dynamics, such as histone modifying enzymes, are not as well-studied. Inhibitors targeting DNA modifying enzymes, particularly histone modifying enzymes represent a potential cancer treatment. Due to the ability of epigenetic therapies to target multiple pathways simultaneously, tumours with complex mutational landscapes affected by multiple driver mutations may be most amenable to this type of inhibitor. Interrogation of the actionable landscape of different gynaecological cancer types has revealed that some patients have biomarkers which indicate potential sensitivity to epigenetic inhibitors. In this review we describe the role of epigenetics in gynaecological cancers and highlight how it may exploited for treatment.

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.

scholarly journals Author Correction: The effects of mutational processes and selection on driver mutations across cancer types

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Daniel Temko ◽  
Ian P. M. Tomlinson ◽  
Simone Severini ◽  
Benjamin Schuster-Böckler ◽  
Trevor A. Graham
Keyword(s):  
Driver Mutations ◽  
Cancer Types ◽  
Mutational Processes

scholarly journals Population sequencing data reveal a compendium of mutational processes in human germline

2020 ◽  
Author(s):  
Vladimir B. Seplyarskiy ◽  
Ruslan A. Soldatov ◽  
Ryan J. McGinty ◽  
Jakob M. Goldmann ◽  
Ryan Hernandez ◽  
...  
Keyword(s):  
Large Scale ◽  
Replication Timing ◽  
Mutagenic Effect ◽  
Dna Lesions ◽  
Sequencing Data ◽  
Biological Interpretation ◽  
Mutagenic Process ◽  
Mutational Processes ◽  
Transcription And Replication

Mechanistic processes underlying human germline mutations remain largely unknown. Variation in mutation rate and spectra along the genome is informative about the biological mechanisms. We statistically decompose this variation into separate processes using a blind source separation technique. The analysis of a large-scale whole genome sequencing dataset (TOPMed) reveals nine processes that explain the variation in mutation properties between loci. Seven of these processes lend themselves to a biological interpretation. One process is driven by bulky DNA lesions that resolve asymmetrically with respect to transcription and replication. Two processes independently track direction of replication fork and replication timing. We identify a mutagenic effect of active demethylation primarily acting in regulatory regions. We also demonstrate that a recently discovered mutagenic process specific to oocytes can be localized solely from population sequencing data. This process is spread across all chromosomes and is highly asymmetric with respect to the direction of transcription, suggesting a major role of DNA damage.

scholarly journals A molecular portrait of microsatellite instability across multiple cancers

2016 ◽  
Author(s):  
Isidro Cortes-Ciriano ◽  
Sejoon Lee ◽  
Woong-Yang Park ◽  
Tae-Min Kim ◽  
Peter J. Park
Keyword(s):  
Microsatellite Instability ◽  
High Sensitivity ◽  
Tumor Type ◽  
Sequencing Data ◽  
Molecular Fingerprints ◽  
Dna Mismatch ◽  
Oncogenic Pathways ◽  
Cancer Types ◽  
Tumor Types ◽  
Pan Cancer

ABSTRACTMicrosatellite instability (MSI) refers to the hypermutability of the cancer genome due to impaired DNA mismatch repair. Although MSI has been studied for decades, the large amount of sequencing data now available allows us to examine the molecular fingerprints of MSI in greater detail. Here, we analyze ~8000 exome and ~1000 whole-genome pairs across 23 cancer types. Our pan-cancer analysis reveals that the prevalence of MSI events is highly variable within and across tumor types including some in which MSI is not typically examined. We also identify genes in DNA repair and oncogenic pathways recurrently subject to MSI and uncover non-coding loci that frequently display MSI events. Finally, we propose an exomebased predictive model for the MSI phenotype that achieves high sensitivity and specificity. These results advance our understanding of the genomic drivers and consequences of MSI, and a comprehensive catalog of tumor-type specific MSI loci we have generated enables efficient panel-based MSI testing to identify patients who are likely to benefit from immunotherapy.

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 Mathematical modeling of multiple pathways in colorectal carcinogenesis using dynamical systems with Kronecker structure

2021 ◽  
Vol 17 (5) ◽  
pp. e1008970
Author(s):  
Saskia Haupt ◽  
Alexander Zeilmann ◽  
Aysel Ahadova ◽  
Hendrik Bläker ◽  
Magnus von Knebel Doeberitz ◽  
...  
Keyword(s):  
Gene Mutation ◽  
System Modeling ◽  
Colorectal Carcinogenesis ◽  
Driver Mutations ◽  
Recent Experimental Data ◽  
Driver Gene ◽  
Dna Mismatch ◽  
Mmr Genes ◽  
Clinical Observations ◽  
Mutational Processes

Like many other types of cancer, colorectal cancer (CRC) develops through multiple pathways of carcinogenesis. This is also true for colorectal carcinogenesis in Lynch syndrome (LS), the most common inherited CRC syndrome. However, a comprehensive understanding of the distribution of these pathways of carcinogenesis, which allows for tailored clinical treatment and even prevention, is still lacking. We suggest a linear dynamical system modeling the evolution of different pathways of colorectal carcinogenesis based on the involved driver mutations. The model consists of different components accounting for independent and dependent mutational processes. We define the driver gene mutation graphs and combine them using the Cartesian graph product. This leads to matrix components built by the Kronecker sum and product of the adjacency matrices of the gene mutation graphs enabling a thorough mathematical analysis and medical interpretation. Using the Kronecker structure, we developed a mathematical model which we applied exemplarily to the three pathways of colorectal carcinogenesis in LS. Beside a pathogenic germline variant in one of the DNA mismatch repair (MMR) genes, driver mutations in APC, CTNNB1, KRAS and TP53 are considered. We exemplarily incorporate mutational dependencies, such as increased point mutation rates after MMR deficiency, and based on recent experimental data, biallelic somatic CTNNB1 mutations as common drivers of LS-associated CRCs. With the model and parameter choice, we obtained simulation results that are in concordance with clinical observations. These include the evolution of MMR-deficient crypts as early precursors in LS carcinogenesis and the influence of variants in MMR genes thereon. The proportions of MMR-deficient and MMR-proficient APC-inactivated crypts as first measure for the distribution among the pathways in LS-associated colorectal carcinogenesis are compatible with clinical observations. The approach provides a modular framework for modeling multiple pathways of carcinogenesis yielding promising results in concordance with clinical observations in LS CRCs.

scholarly journals The effects of mutational processes and selection on driver mutations across cancer types

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Daniel Temko ◽  
Ian P. M. Tomlinson ◽  
Simone Severini ◽  
Benjamin Schuster-Böckler ◽  
Trevor A. Graham
Keyword(s):  
Driver Mutations ◽  
Cancer Types ◽  
Mutational Processes

scholarly journals A comprehensive characterization of cis-acting splicing-associated variants in human cancer

2017 ◽  
Author(s):  
Yuichi Shiraishi ◽  
Keisuke Kataoka ◽  
Kenichi Chiba ◽  
Ai Okada ◽  
Yasunori Kogure ◽  
...  
Keyword(s):  
Splice Site ◽  
Human Cancer ◽  
Intron Retention ◽  
Exon Skipping ◽  
Driver Mutations ◽  
Splice Sites ◽  
Sequencing Data ◽  
Cis Acting ◽  
Statistical Framework ◽  
Cancer Types

AbstractAlthough many driver mutations are thought to promote carcinogenesis via abnormal splicing, the landscape of these splicing-associated variants (SAVs) remains unknown due to the complexity of splicing abnormalities. Here we developed a statistical framework to identify SAVs disrupting or newly creating splice site motifs and applied it to sequencing data from 8,976 samples across 31 cancer types. We constructed a catalog of 14,438 SAVs, approximately 50% of which consist of SAVs disrupting non-canonical splice sites (including the 3rd and 5th intronic bases of donor sites) or newly creating splice sites. Smoking-related signature substantially contributes to SAV generation. As many as 14.7% of samples harbor at least one SAVs in cancer-related genes, particularly in tumor suppressors. Importantly, in addition to previously reported intron retention, exon skipping or alternative splice site usage more frequently affected these genes. Our findings delineate a comprehensive portrait of SAVs, providing a basis for cancer precision medicine.

scholarly journals DDRE-09. THERAPEUTIC TARGETING OF PURINE METABOLISM IN DIPG

2021 ◽  
Vol 3 (Supplement_1) ◽  
pp. i8-i8
Author(s):  
Ian Mersich ◽  
Biplab Dasgupta
Keyword(s):  
Overall Survival ◽  
Cell Lines ◽  
De Novo ◽  
Cell Types ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Purine Metabolism ◽  
Driver Mutations ◽  
Sequencing Data ◽  
Metabolomics Analysis

Abstract Diffuse intrinsic pontine glioma (DIPG) is an incurable brainstem malignancy in children with median survival less than 1 year and 5-year overall survival only 2 percent. Little progress has been made in treating this deadly disease due to its inoperable location and treatments aimed at targets defined in adult gliomas. Despite recent advances in genetic characterization of DIPGs there are still no targeted therapies that significantly improve overall survival. We recently generated a metabolic profile for patient-derived DIPG cell lines by integrating an untargeted metabolomics analysis with RNA-sequencing data from the same lines which demonstrated dysregulated purine metabolism in these cells. Furthermore, we have identified putative driver mutations common to DIPG patients as the direct cause for this metabolic alteration. Purine metabolism provides the basic components of nucleotides needed for tumor proliferation and thus considered a high-priority target in cancer treatment. De novo purine biosynthesis (DNPS) is a sequential ten step enzymatic process resulting in the production of inosine monophosphate. The DNPS enzymes co-localize into a metabolon known as the purinosome and our preliminary data demonstrates DIPG cell lines are selectively sensitive to pharmacological and genetic disruption of purinosome formation. Interestingly, antifolate compounds that inhibit DNPS, but do not disrupt purinosome assembly, are cytotoxic to both DIPG cells and normal cell types. Strikingly, cell viability could be rescued by purine supplementation when inhibiting this pathway with antifolates, however inhibition of DNPS by disruption of purinosome assembly could not be rescued. Metabolomics analysis showed DIPGs have a preference for generating GMP over AMP which is exacerbated when purinosome assembly is disrupted. This is likely due to the duel-role of the DNPS enzyme ADSL which is required for AMP production.

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