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 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.

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 Mutational signatures associated with tobacco smoking in human cancer

2016 ◽  
Author(s):  
Ludmil B. Alexandrov ◽  
Young Seok Ju ◽  
Kerstin Haase ◽  
Peter Van Loo ◽  
Iñigo Martincorena ◽  
...  
Keyword(s):  
Tobacco Smoke ◽  
Tobacco Smoking ◽  
Human Cancer ◽  
Mutational Signatures ◽  
Cytidine Deaminases ◽  
Endogenous Clock ◽  
Cancer Types ◽  
Tobacco Carcinogens ◽  
Mutational Processes ◽  
Mutational Process

ABSTRACTTobacco smoking increases the risk of at least 15 classes of cancer. We analyzed somatic mutations and DNA methylation in 5,243 cancers of types for which tobacco smoking confers an elevated risk. Smoking is associated with increased mutation burdens of multiple distinct mutational signatures, which contribute to different extents in different cancers. One of these signatures, mainly found in cancers derived from tissues directly exposed to tobacco smoke, is attributable to misreplication of DNA damage caused by tobacco carcinogens. Others likely reflect indirect activation of DNA editing by APOBEC cytidine deaminases and of an endogenous clock-like mutational process. The results are consistent with the proposition that smoking increases cancer risk by increasing the somatic mutation load, although direct evidence for this mechanism is lacking in some smoking-related cancer types.ONE SENTENCE SUMMARYMultiple distinct mutational processes associate with tobacco smoking in cancer reflecting direct and indirect effects of tobacco smoke.

scholarly journals MutEx: a multifaceted gateway for exploring integrative pan-cancer genomic data

2019 ◽  
Vol 21 (4) ◽  
pp. 1479-1486 ◽  
Author(s):  
Jie Ping ◽  
Olufunmilola Oyebamiji ◽  
Hui Yu ◽  
Scott Ness ◽  
Jeremy Chien ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Somatic Mutation ◽  
Survival Data ◽  
Somatic Mutations ◽  
Genomic Data ◽  
Mismatch Repair Gene ◽  
Survival Difference ◽  
Cancer Types ◽  
Pan Cancer

Abstract Somatic mutation and gene expression dysregulation are considered two major tumorigenesis factors. While independent investigations of either factor pervade, studies of associations between somatic mutations and gene expression changes have been sporadic and nonsystematic. Utilizing genomic data collected from 11 315 subjects of 33 distinct cancer types, we constructed MutEx, a pan-cancer integrative genomic database. This database records the relationships among gene expression, somatic mutation and survival data for cancer patients. MutEx can be used to swiftly explore the relationship between these genomic/clinic features within and across cancer types and, more importantly, search for corroborating evidence for hypothesis inception. Our database also incorporated Gene Ontology and several pathway databases to enhance functional annotation, and elastic net and a gene expression composite score to aid in survival analysis. To demonstrate the usability of MutEx, we provide several application examples, including top somatic mutations associated with the most extensive expression dysregulation in breast cancer, differential mutational burden downstream of DNA mismatch repair gene mutations and composite gene expression score-based survival difference in breast cancer. MutEx can be accessed at http://www.innovebioinfo.com/Databases/Mutationdb_About.php.

scholarly journals Mutational likeliness and entropy help to identify driver mutations and their functional role in cancer

2018 ◽  
Author(s):  
Giorgio Mattiuz ◽  
Salvatore Di Giorgio ◽  
Lorenzo Tofani ◽  
Antonio Frandi ◽  
Francesco Donati ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Somatic Mutations ◽  
Driver Mutations ◽  
Cancer Evolution ◽  
Loss Of Function ◽  
Driver Genes ◽  
Cancer Driver ◽  
Cancer Genomes ◽  
Passenger Mutations ◽  
Mutational Processes

AbstractAlterations in cancer genomes originate from mutational processes taking place throughout oncogenesis and cancer progression. We show that likeliness and entropy are two properties of somatic mutations crucial in cancer evolution, as cancer-driver mutations stand out, with respect to both of these properties, as being distinct from the bulk of passenger mutations. Our analysis can identify novel cancer driver genes and differentiate between gain and loss of function mutations.

scholarly journals The impact of rare germline variants on human somatic mutation processes

2021 ◽  
Author(s):  
Mischan Vali-Pour ◽  
Ben Lehner ◽  
Fran Supek
Keyword(s):  
Somatic Mutation ◽  
Human Cancer ◽  
European Ancestry ◽  
Novel Genes ◽  
Data Set ◽  
Dna Mismatch ◽  
Repair Deficiency ◽  
Germline Variation ◽  
The Impact ◽  
Mutational Processes

Somatic mutations are an inevitable component of ageing and the most important cause of cancer. The rates and types of somatic mutation vary across individuals, but relatively few inherited influences on mutation processes are known. We performed a comprehensive gene-based rare variant association study with diverse mutational processes, using human cancer genomes from over 11,000 individuals of European ancestry. By combining burden and variance tests, we identify 207 associations involving 15 somatic mutational phenotypes and 42 genes that replicated in an independent data set at a FDR of 1%. We associated rare inherited deleterious variants in novel genes such as MSH3, EXO1, SETD2, and MTOR with two different forms of DNA mismatch repair deficiency, and variants in genes such as EXO1, PAXIP1, and WRN with deficiency in homologous recombination repair. In addition, we identified associations with other mutational processes, such as APEX1 with APOBEC-signature mutagenesis. Many of the novel genes interact with each other and with known mutator genes within cellular sub-networks. Considered collectively, damaging variants in the newly-identified genes are prevalent in the population. We suggest that rare germline variation in diverse genes commonly impacts mutational processes in somatic cells.

scholarly journals ROKET: Associating Somatic Mutation with Clinical Outcomes through Kernel Regression and Optimal Transport

2021 ◽  
Author(s):  
Paul Little ◽  
Li Hsu ◽  
Wei Sun
Keyword(s):  
Cancer Patients ◽  
Clinical Outcomes ◽  
Somatic Mutation ◽  
Somatic Mutations ◽  
Optimal Transport ◽  
Kernel Regression ◽  
Multiple Genes ◽  
Cancer Types ◽  
Mutation Data ◽  
Gene Similarity

Somatic mutations in cancer patients are inherently sparse and potentially high dimensional. Cancer patients may share the same set of deregulated biological processes perturbed by different sets of somatically mutated genes. Therefore, when assessing the associations between somatic mutations and clinical outcomes, gene-by-gene analyses is often under-powered because it does not capture the complex disease mechanisms shared across cancer patients. Rather than testing genes one by one, an intuitive approach is to aggregate somatic mutation data of multiple genes to assess the joint association. The challenge is how to aggregate such information. Building on the optimal transport method, we propose a principled approach to estimate the similarity of somatic mutation profiles of multiple genes between tumor samples, while accounting for gene-gene similarity defined by gene annotations or empirical mutational patterns. Using such similarities, we can assess the associations between somatic mutations and clinical outcomes by kernel regression. We have applied our method to analyze somatic mutation data of 17 cancer types and identified at least three cancer types harboring associations between somatic mutations and overall survival, progression-free interval or cytolytic activity.

scholarly journals Patterns of Somatic Mutations in Immunoglobulin Variable Genes

Genetics ◽  
1987 ◽  
Vol 115 (1) ◽  
pp. 169-176
Author(s):  
G Brian Golding ◽  
Patricia J Gearhart ◽  
Barry W Glickman
Keyword(s):  
Somatic Mutation ◽  
Dna Sequences ◽  
Somatic Mutations ◽  
Nucleotide Substitutions ◽  
Immunoglobulin Variable Genes ◽  
Variable Gene ◽  
Meiotic Mutations ◽  
Mutational Processes ◽  
Palindromic Sequences ◽  
Variable Genes

ABSTRACT The mechanism responsible for somatic mutation in the variable genes of antibodies is unknown and may differ from previously described mechanisms that produce mutation in DNA. We have analyzed 421 somatic mutations from the rearranged immunoglobulin variable genes of mice to determine (1) if the nucleotide substitutions differ from those generated during meiosis and (2) if the presence of nearby direct and inverted repeated sequences could template mutations around the variable gene. The results reveal a difference in the pattern of substitutions obtained from somatic mutations vs. meiotic mutations. An increased frequency of T:A to C:G transitions and a decreased frequency of mutations involving a G in the somatic mutants compared to the meiotic mutants is indicated. This suggests that the mutational processes responsible for somatic mutation in antibody genes differs from that responsible for mutation during meiosis. An analysis of the local DNA sequences revealed many direct repeats and palindromic sequences that were capable of templating some of the known mutations. Although additional factors may be involved in targeting mutations to the variable gene, mistemplating by nearby repeats may provide a mechanism for the enhancement of somatic mutation.

scholarly journals Abnormal Expressions of DNA Glycosylase Genes NEIL1, NEIL2, and NEIL3 Are Associated with Somatic Mutation Loads in Human Cancer

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Kazuya Shinmura ◽  
Hisami Kato ◽  
Yuichi Kawanishi ◽  
Hisaki Igarashi ◽  
Masanori Goto ◽  
...  
Keyword(s):  
Somatic Mutation ◽  
Human Cancer ◽  
Promoter Hypermethylation ◽  
The Cancer Genome Atlas ◽  
Expression Level ◽  
Dna Glycosylases ◽  
Potent Inducer ◽  
Nucleotide Mutation ◽  
Cancer Types ◽  
Using Data

The effects of abnormalities in the DNA glycosylases NEIL1, NEIL2, and NEIL3 on human cancer have not been fully elucidated. In this paper, we found that the median somatic total mutation loads and the median somatic single nucleotide mutation loads exhibited significant inverse correlations with the median NEIL1 and NEIL2 expression levels and a significant positive correlation with the median NEIL3 expression level using data for 13 cancer types from the Cancer Genome Atlas (TCGA) database. A subset of the cancer types exhibited reduced NEIL1 and NEIL2 expressions and elevated NEIL3 expression, and such abnormal expressions of NEIL1, NEIL2, and NEIL3 were also significantly associated with the mutation loads in cancer. As a mechanism underlying the reduced expression of NEIL1 in cancer, the epigenetic silencing ofNEIL1through promoter hypermethylation was found. Finally, we investigated the reason why an elevated NEIL3 expression level was associated with an increased number of somatic mutations in cancer and found that NEIL3 expression was positively correlated with the expression of APOBEC3B, a potent inducer of mutations, in diverse cancers. These results suggested that the abnormal expressions of NEIL1, NEIL2, and NEIL3 are involved in cancer through their association with the somatic mutation load.

scholarly journals Pan-Cancer Analysis Reveals Differential Susceptibility of Bidirectional Gene Promoters to DNA Methylation, Somatic Mutations, and Copy Number Alterations

2018 ◽  
Author(s):  
Jeffrey A. Thompson ◽  
Brock C. Christensen ◽  
Carmen J. Marsit
Keyword(s):  
Dna Methylation ◽  
Logistic Regression ◽  
Somatic Mutation ◽  
Copy Number ◽  
Copy Number Alteration ◽  
Somatic Mutations ◽  
Gene Promoters ◽  
Bidirectional Promoters ◽  
Somatic Alteration ◽  
Cancer Types

Bidirectional gene promoters affect the transcription of two genes, leading to the hypothesis that they should exhibit protection against genetic or epigenetic changes in cancer. Therefore, they provide an excellent opportunity to learn about promoter susceptibility to somatic alteration in tumors. We tested this hypothesis using data from genome-scale DNA methylation (14 cancer types), simple somatic mutation (10 cancer types), and copy number variation profiling (14 cancer types). For DNA methylation, the difference in rank differential methylation between tumor and tumor-adjacent normal matched samples based on promoter type was tested by Wilcoxon rank sum test. Logistic regression was used to compare differences in simple somatic mutations. For copy number alteration, a mixed effects logistic regression model was used. The change in methylation between non-diseased tissues and their tumor counterparts was significantly greater in single compared to bidirectional promoters across all 14 cancer types examined. Similarly, the extent of copy number alteration was greater in single gene compared to bidirectional promoters for all 14 cancer types. Furthermore, among 10 cancer types with available simple somatic mutation data, bidirectional promoters were slightly more susceptible. These results suggest that selective pressures related with specific functional impacts during carcinogenesis drive the susceptibility of promoter regions to somatic alteration.

Sign in / Sign up

Export Citation Format

Share Document