scholarly journals Learning mutational signatures and their multidimensional genomic properties with TensorSignatures

2019 ◽  
Author(s):  
Harald Vöhringer ◽  
Arne van Hoeck ◽  
Edwin Cuppen ◽  
Moritz Gerstung
Keyword(s):  
Somatic Hypermutation ◽  
Translesion Synthesis ◽  
Strand Break ◽  
Signature Analysis ◽  
Transcription Start ◽  
Mutational Signatures ◽  
Transcription Start Sites ◽  
Mutational Signature ◽  
Cancer Genomes ◽  
Cancer Types

AbstractMutational signature analysis is an essential part of the cancer genome analysis toolkit. Conventionally, mutational signature analysis extracts patterns of different mutation types across many cancer genomes. Here we present TensorSignatures, an algorithm to learn mutational signatures jointly across all variant categories and their genomic context. The analysis of 2,778 primary and 3,824 metastatic cancer genomes of the PCAWG consortium and the HMF cohort shows that practically all signatures operate dynamically in response to various genomic and epigenomic states. The analysis pins differential spectra of UV mutagenesis found in active and inactive chromatin to global genome nucleotide excision repair. TensorSignatures accurately characterises transcription-associated mutagenesis, which is detected in 7 different cancer types. The analysis also unmasks replication- and double strand break repair-driven APOBEC mutagenesis, which manifests with differential numbers and length of mutation clusters indicating a differential processivity of the two triggers. As a fourth example, TensorSignatures detects a signature of somatic hypermutation generating highly clustered variants around the transcription start sites of active genes in lymphoid leukaemia, distinct from a more general and less clustered signature of Polη-driven translesion synthesis found in a broad range of cancer types.Key findingsSimultaneous inference of mutational signatures across mutation types and genomic features refines signature spectra and defines their genomic determinants.Analysis of 6,602 cancer genomes reveals pervasive intra-genomic variation of mutational processes.Distinct mutational signatures found in quiescent and active regions of the genome reveal differential repair and mutagenicity of UV- and tobacco-induced DNA damage.APOBEC mutagenesis produces two signatures reflecting highly clustered, double strand break repair-initiated and lowly clustered replication-driven mutagenesis, respectively.Somatic hypermutation in lymphoid cancers produces a strongly clustered mutational signature localised to transcription start sites, which is distinct from a weakly clustered translesion synthesis signature found in multiple tumour types.

scholarly journals Learning mutational signatures and their multidimensional genomic properties with TensorSignatures

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Harald Vöhringer ◽  
Arne Van Hoeck ◽  
Edwin Cuppen ◽  
Moritz Gerstung
Keyword(s):  
Somatic Hypermutation ◽  
Excision Repair ◽  
Metastatic Cancer ◽  
Strand Break ◽  
Lymphoid Leukaemia ◽  
Mutational Signatures ◽  
Transcription Start Sites ◽  
Nucleotide Excision ◽  
Cancer Types ◽  
Underlying Processes

AbstractWe present TensorSignatures, an algorithm to learn mutational signatures jointly across different variant categories and their genomic localisation and properties. The analysis of 2778 primary and 3824 metastatic cancer genomes of the PCAWG consortium and the HMF cohort shows that all signatures operate dynamically in response to genomic states. The analysis pins differential spectra of UV mutagenesis found in active and inactive chromatin to global genome nucleotide excision repair. TensorSignatures accurately characterises transcription-associated mutagenesis in 7 different cancer types. The algorithm also extracts distinct signatures of replication- and double strand break repair-driven mutagenesis by APOBEC3A and 3B with differential numbers and length of mutation clusters. Finally, TensorSignatures reproduces a signature of somatic hypermutation generating highly clustered variants at transcription start sites of active genes in lymphoid leukaemia, distinct from a general and less clustered signature of Polη-driven translesion synthesis found in a broad range of cancer types. In summary, TensorSignatures elucidates complex mutational footprints by characterising their underlying processes with respect to a multitude of genomic variables.

scholarly journals MetaMutationalSigs: Comparison of mutational signature refitting results made easy

2021 ◽  
Author(s):  
Palash Pandey ◽  
Sanjeevani Arora ◽  
Gail Rosen
Keyword(s):  
Cancer Genetics ◽  
Research Question ◽  
Treatment Decision ◽  
Signature Analysis ◽  
Cancer Evolution ◽  
Mutational Signatures ◽  
Mutational Signature ◽  
Specific Research Question ◽  
Cancer Types ◽  
User Friendly

The analysis of mutational signatures is becoming increasingly common in cancer genetics, with emerging implications in cancer evolution, classification, treatment decision and prognosis. Recently, several packages have been developed for mutational signature analysis, with each using different methodology and yielding significantly different results. Because of the nontrivial differences in tools' refitting results, researchers may desire to survey and compare the available tools, in order to objectively evaluate the results for their specific research question, such as which mutational signatures are prevalent in different cancer types. There is a need for a software that can aggregate results from different refitting packages and present them in a user-friendly way to facilitate effective comparison of mutational signatures.

scholarly journals Impact of cancer mutational signatures on transcription factor motifs in the human genome

2018 ◽  
Author(s):  
Calvin Wing Yiu Chan ◽  
Zuguang Gu ◽  
Matthias Bieg ◽  
Roland Eils ◽  
Carl Herrmann
Keyword(s):  
Transcription Factor ◽  
Information Content ◽  
Molecular Mechanisms ◽  
Reference Dataset ◽  
Mutational Signatures ◽  
Binding Motifs ◽  
Background Estimation ◽  
Cancer Genomes ◽  
Cancer Types ◽  
Tfbs Motif

ABSTRACTBackgroundSomatic mutations in cancer genomes occur through a variety of molecular mechanisms, which contribute to different mutational patterns. To summarize these, mutational signatures have been defined using a large number of cancer genomes, and related to distinct mutagenic processes. Each cancer genome can be compared to this reference dataset and its exposure to one or the other signature be determined. Given the very different mutational patterns of these signatures, we anticipate that they will have distinct impact on genomic elements, in particular motifs for transcription factor binding sites (TFBS).ResultsIn this work, we build the link between mutational signatures and TFBS motif alterations. We investigated and computed the theoretical impact of mutational signatures on 512 TFBS motifs, hence translating the trinucleotide mutation frequencies of the signatures into alteration frequencies of specific TFBS motifs, leading either to creation of disruption of these motifs. We further build a theoretical prediction of the alteration patterns for different cancer types based on the exposure of these cancer types to the mutation signatures. For certain motifs, a high correlation is observed between the TFBS motif creation and disruption events related to the information content of the motif.ConclusionOur results show that the mutational signatures have different impact on the binding motifs of transcription factors and that for certain high complexity motifs there is a strong correlation between creation and disruption, related to the information content of the motif. This study represents a background estimation of the alterations due purely to mutational signatures in the absence of additional contributions, e.g. from evolutionary processes.

scholarly journals sigfit: flexible Bayesian inference of mutational signatures

2018 ◽  
Author(s):  
Kevin Gori ◽  
Adrian Baez-Ortega
Keyword(s):  
Bayesian Inference ◽  
Probabilistic Models ◽  
R Package ◽  
Signature Analysis ◽  
Mutational Signatures ◽  
Mutational Spectra ◽  
Mutational Signature ◽  
Linear Optimisation ◽  
Biological Patterns ◽  
User Friendly

Mutational signature analysis aims to infer the mutational spectra and relative exposures of processes that contribute mutations to genomes. Different models for signature analysis have been developed, mostly based on non-negative matrix factorisation or non-linear optimisation. Here we present sigfit, an R package for mutational signature analysis that applies Bayesian inference to perform fitting and extraction of signatures from mutation data. We compare the performance of sigfit to prominent existing software, and find that it compares favourably. Moreover, sigfit introduces novel probabilistic models that enable more robust, powerful and versatile fitting and extraction of mutational signatures and broader biological patterns. The package also provides user-friendly visualisation routines and is easily integrable with other bioinformatic packages.

scholarly journals Global Autozygosity Is Associated with Cancer Risk, Mutational Signature and Prognosis

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3646
Author(s):  
Limin Jiang ◽  
Fei Guo ◽  
Jijun Tang ◽  
Shuguan Leng ◽  
Scott Ness ◽  
...  
Keyword(s):  
Cancer Risk ◽  
Invasive Carcinoma ◽  
Cancer Risk Assessment ◽  
Mutational Signatures ◽  
Survival Analyses ◽  
Mutational Signature ◽  
Genome Wide ◽  
Cancer Types ◽  
Male Skin ◽  
Disease Specific

Global autozygosity quantifies the genome-wide levels of homozygous and heterozygous variants. It is the signature of non-random reproduction, though it can also be driven by other factors, and has been used to assess risk in various diseases. However, the association between global autozygosity and cancer risk has not been studied. From 4057 cancer subjects and 1668 healthy controls, we found strong associations between global autozygosity and risk in ten different cancer types. For example, the heterozygosity ratio was found to be significantly associated with breast invasive carcinoma in Blacks and with male skin cutaneous melanoma in Caucasians. We also discovered eleven associations between global autozygosity and mutational signatures which can explain a portion of the etiology. Furthermore, four significant associations for heterozygosity ratio were revealed in disease-specific survival analyses. This study demonstrates that global autozygosity is effective for cancer risk assessment.

scholarly journals A framework for mutational signature analysis based on DNA shape parameters

PLoS ONE ◽  
2022 ◽  
Vol 17 (1) ◽  
pp. e0262495
Author(s):  
Aleksandra Karolak ◽  
Jurica Levatić ◽  
Fran Supek
Keyword(s):  
Dna Repair ◽  
Base Pair ◽  
Mutation Frequency ◽  
Structural Features ◽  
Sequence Motif ◽  
Signature Analysis ◽  
Mutational Signatures ◽  
Radiation Chemical ◽  
Mutational Signature ◽  
Dna Shape

The mutation risk of a DNA locus depends on its oligonucleotide context. In turn, mutability of oligonucleotides varies across individuals, due to exposure to mutagenic agents or due to variable efficiency and/or accuracy of DNA repair. Such variability is captured by mutational signatures, a mathematical construct obtained by a deconvolution of mutation frequency spectra across individuals. There is a need to enhance methods for inferring mutational signatures to make better use of sparse mutation data (e.g., resulting from exome sequencing of cancers), to facilitate insight into underlying biological mechanisms, and to provide more accurate mutation rate baselines for inferring positive and negative selection. We propose a conceptualization of mutational signatures that represents oligonucleotides via descriptors of DNA conformation: base pair, base pair step, and minor groove width parameters. We demonstrate how such DNA structural parameters can accurately predict mutation occurrence due to DNA repair failures or due to exposure to diverse mutagens such as radiation, chemical exposure, and the APOBEC cytosine deaminase enzymes. Furthermore, the mutation frequency of DNA oligomers classed by structural features can accurately capture systematic variability in mutagenesis of >1,000 tumors originating from diverse human tissues. A nonnegative matrix factorization was applied to mutation spectra stratified by DNA structural features, thereby extracting novel mutational signatures. Moreover, many of the known trinucleotide signatures were associated with an additional spectrum in the DNA structural descriptor space, which may aid interpretation and provide mechanistic insight. Overall, we suggest that the power of DNA sequence motif-based mutational signature analysis can be enhanced by drawing on DNA shape features.

scholarly journals Performance Characteristics of Mutational Signature Analysis in Targeted Panel Sequencing

2021 ◽  
Author(s):  
Lauren Lawrence ◽  
Christian A. Kunder ◽  
Eula Fung ◽  
Henning Stehr ◽  
James Zehnder
Keyword(s):  
Ultraviolet Radiation ◽  
Tobacco Smoking ◽  
High Specificity ◽  
Primary Site ◽  
Clinical Samples ◽  
Signature Analysis ◽  
Mutational Signatures ◽  
Targeted Next Generation Sequencing ◽  
Mutational Signature ◽  
Poorly Differentiated

Context.— Mutational signatures have been described in the literature and a few centers have implemented pipelines for clinical reporting. Objective.— To describe the performance of a mutational signature caller with clinical samples sequenced on a targeted next-generation sequencing panel with a small genomic footprint. Design.— One thousand six hundred eighty-two (n = 1682) clinical samples were analyzed for the presence of mutational signatures using deconstructSigs on variant calls with at least 20 variant reads. Results.— Signature 10 (associated with POLe mutation) achieved separation of cases and controls in hypermutated samples. Signatures 4 (associated with tobacco smoking) and 7 (associated with ultraviolet radiation) as an indicator of pulmonary or cutaneous primary sites showed moderate sensitivity and high specificity at optimal cutpoints. Mutational signatures in malignancies with unknown primaries were somewhat consistent with the clinically suspected primary site, with an apparent dose-response relationship between the number of variants analyzed and the ability of mutational signature analysis to correctly suggest a primary site. Conclusions.— Mutational signatures represent an opportunity for orthogonal testing of primary site, which may be particularly useful in supporting cutaneous or pulmonary sites in poorly differentiated neoplasms. Tobacco smoking, ultraviolet radiation, and POLe mutational signatures are the most appropriate signatures for implementation. Even relatively small numbers of variants appear capable of supporting a clinically suspected primary.

scholarly journals A framework for mutational signature analysis based on DNA shape parameters

2020 ◽  
Author(s):  
Aleksandra Karolak ◽  
Fran Supek
Keyword(s):  
Dna Repair ◽  
Base Pair ◽  
Mutation Frequency ◽  
Chemical Exposure ◽  
Signature Analysis ◽  
Mutational Signatures ◽  
Frequency Spectra ◽  
Radiation Chemical ◽  
Mutational Signature ◽  
Dna Shape

AbstractThe propensity to acquire mutations depends on the oligonucleotide context of a DNA locus. In turn, this differential mutability of oligonucleotides varies across individuals due to exposure to mutagenic agents or due to variable efficiency of DNA repair pathways. Such variability is captured by mutational signatures, mathematical constructs resulting from a deconvolution of mutation frequency spectra across individuals. There is a need to enhance methods for inferring mutational signatures to make better use of sparse mutation frequency data that results from genome sequencing, and additionally to facilitate insight into underlying biological mechanisms. In cancer genomics, novel approaches to analyze somatic mutation patterns may help explain the etiology of various tumor types, as well as provide a more accurate baseline to infer positive and negative selection on somatic changes that drive tumor evolution. We propose a conceptualization of mutational signatures that represents oligonucleotides via descriptors of DNA conformation: base pair, base pair step, and minor groove width parameters. We demonstrate how such DNA structural parameters can accurately predict mutation occurrence due to DNA repair failures or due to exposure to diverse mutagens, including radiation, chemical exposure and the APOBEC cytosine deaminase enzymes. Furthermore, the mutation frequency of DNA oligomers classed by structural features can accurately capture systematic variability in mutational spectra of >1,000 tumors originating from diverse human tissues. Overall, we suggest that the power of DNA sequence-based mutational signature analysis can be enhanced by drawing on DNA shape features.

scholarly journals mutSigMapper: an R package to map spectra to mutational signatures based on shot-noise modeling

2020 ◽  
Author(s):  
Julián Candia
Keyword(s):  
Shot Noise ◽  
Statistical Significance ◽  
R Package ◽  
Signature Analysis ◽  
Mutational Signatures ◽  
Noise Modeling ◽  
Mutational Signature ◽  
Link Type ◽  
Non Parametric

AbstractSummarymutSigMapper aims to resolve a critical shortcoming of existing software for mutational signature analysis, namely that of finding parsimonious and biologically plausible exposures. By implementing a shot-noise-based model to generate spectral ensembles, this package addresses this gap and provides a quantitative, non-parametric assessment of statistical significance for the association between mutational signatures and observed spectra.Availability and implementationThe mutSigMapper R package is available under GPLv3 license at https://github.com/juliancandia/mutSigMapper. Its documentation provides additional details and demonstrates applications to biological datasets.

scholarly journals mmsig: a fitting approach to accurately identify somatic mutational signatures in hematological malignancies

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Even H. Rustad ◽  
Ferran Nadeu ◽  
Nicos Angelopoulos ◽  
Bachisio Ziccheddu ◽  
Niccolò Bolli ◽  
...  
Keyword(s):  
Dynamic Error ◽  
R Package ◽  
Biological Knowledge ◽  
Mutational Signatures ◽  
Cytidine Deaminases ◽  
Therapeutic Implications ◽  
Mutational Signature ◽  
Fitting Algorithm ◽  
Cancer Genomes

AbstractMutational signatures have emerged as powerful biomarkers in cancer patients, with prognostic and therapeutic implications. Wider clinical utility requires access to reproducible algorithms, which allow characterization of mutational signatures in a given tumor sample. Here, we show how mutational signature fitting can be applied to hematological cancer genomes to identify biologically and clinically important mutational processes, highlighting the importance of careful interpretation in light of biological knowledge. Our newly released R package mmsig comes with a dynamic error-suppression procedure that improves specificity in important clinical and biological settings. In particular, mmsig allows accurate detection of mutational signatures with low abundance, such as those introduced by APOBEC cytidine deaminases. This is particularly important in the most recent mutational signature reference (COSMIC v3.1) where each signature is more clearly defined. Our mutational signature fitting algorithm mmsig is a robust tool that can be implemented immediately in the clinic.

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