A Simple Model-Based Approach to Inferring and Visualizing Cancer Mutation Signatures

Recent advances in sequencing technologies have enabled the production of massive amounts of data on somatic mutations from cancer genomes. These data have led to the detection of characteristic patterns of somatic mutations or "mutation signatures" at an unprecedented resolution, with the...

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Vydané v:PLoS genetics Ročník 11; číslo 12; s. e1005657
Hlavní autori: Shiraishi, Yuichi, Tremmel, Georg, Miyano, Satoru, Stephens, Matthew
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: United States Public Library of Science 01.12.2015
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Abstract Recent advances in sequencing technologies have enabled the production of massive amounts of data on somatic mutations from cancer genomes. These data have led to the detection of characteristic patterns of somatic mutations or "mutation signatures" at an unprecedented resolution, with the potential for new insights into the causes and mechanisms of tumorigenesis. Here we present new methods for modelling, identifying and visualizing such mutation signatures. Our methods greatly simplify mutation signature models compared with existing approaches, reducing the number of parameters by orders of magnitude even while increasing the contextual factors (e.g. the number of flanking bases) that are accounted for. This improves both sensitivity and robustness of inferred signatures. We also provide a new intuitive way to visualize the signatures, analogous to the use of sequence logos to visualize transcription factor binding sites. We illustrate our new method on somatic mutation data from urothelial carcinoma of the upper urinary tract, and a larger dataset from 30 diverse cancer types. The results illustrate several important features of our methods, including the ability of our new visualization tool to clearly highlight the key features of each signature, the improved robustness of signature inferences from small sample sizes, and more detailed inference of signature characteristics such as strand biases and sequence context effects at the base two positions 5' to the mutated site. The overall framework of our work is based on probabilistic models that are closely connected with "mixed-membership models" which are widely used in population genetic admixture analysis, and in machine learning for document clustering. We argue that recognizing these relationships should help improve understanding of mutation signature extraction problems, and suggests ways to further improve the statistical methods. Our methods are implemented in an R package pmsignature (https://github.com/friend1ws/pmsignature) and a web application available at https://friend1ws.shinyapps.io/pmsignature_shiny/.
AbstractList Recent advances in sequencing technologies have enabled the production of massive amounts of data on somatic mutations from cancer genomes. These data have led to the detection of characteristic patterns of somatic mutations or "mutation signatures" at an unprecedented resolution, with the potential for new insights into the causes and mechanisms of tumorigenesis. Here we present new methods for modelling, identifying and visualizing such mutation signatures. Our methods greatly simplify mutation signature models compared with existing approaches, reducing the number of parameters by orders of magnitude even while increasing the contextual factors (e.g. the number of flanking bases) that are accounted for. This improves both sensitivity and robustness of inferred signatures. We also provide a new intuitive way to visualize the signatures, analogous to the use of sequence logos to visualize transcription factor binding sites. We illustrate our new method on somatic mutation data from urothelial carcinoma of the upper urinary tract, and a larger dataset from 30 diverse cancer types. The results illustrate several important features of our methods, including the ability of our new visualization tool to clearly highlight the key features of each signature, the improved robustness of signature inferences from small sample sizes, and more detailed inference of signature characteristics such as strand biases and sequence context effects at the base two positions 5' to the mutated site. The overall framework of our work is based on probabilistic models that are closely connected with "mixed-membership models" which are widely used in population genetic admixture analysis, and in machine learning for document clustering. We argue that recognizing these relationships should help improve understanding of mutation signature extraction problems, and suggests ways to further improve the statistical methods. Our methods are implemented in an R package pmsignature (
  Recent advances in sequencing technologies have enabled the production of massive amounts of data on somatic mutations from cancer genomes. These data have led to the detection of characteristic patterns of somatic mutations or "mutation signatures" at an unprecedented resolution, with the potential for new insights into the causes and mechanisms of tumorigenesis. Here we present new methods for modelling, identifying and visualizing such mutation signatures. Our methods greatly simplify mutation signature models compared with existing approaches, reducing the number of parameters by orders of magnitude even while increasing the contextual factors (e.g. the number of flanking bases) that are accounted for. This improves both sensitivity and robustness of inferred signatures. We also provide a new intuitive way to visualize the signatures, analogous to the use of sequence logos to visualize transcription factor binding sites. We illustrate our new method on somatic mutation data from urothelial carcinoma of the upper urinary tract, and a larger dataset from 30 diverse cancer types. The results illustrate several important features of our methods, including the ability of our new visualization tool to clearly highlight the key features of each signature, the improved robustness of signature inferences from small sample sizes, and more detailed inference of signature characteristics such as strand biases and sequence context effects at the base two positions 5' to the mutated site. The overall framework of our work is based on probabilistic models that are closely connected with "mixed-membership models" which are widely used in population genetic admixture analysis, and in machine learning for document clustering. We argue that recognizing these relationships should help improve understanding of mutation signature extraction problems, and suggests ways to further improve the statistical methods. Our methods are implemented in an R package pmsignature (https://github.com/friend1ws/pmsignature) and a web application available at https://friend1ws.shinyapps.io/pmsignature_shiny/.
Recent advances in sequencing technologies have enabled the production of massive amounts of data on somatic mutations from cancer genomes. These data have led to the detection of characteristic patterns of somatic mutations or "mutation signatures" at an unprecedented resolution, with the potential for new insights into the causes and mechanisms of tumorigenesis. Here we present new methods for modelling, identifying and visualizing such mutation signatures. Our methods greatly simplify mutation signature models compared with existing approaches, reducing the number of parameters by orders of magnitude even while increasing the contextual factors (e.g. the number of flanking bases) that are accounted for. This improves both sensitivity and robustness of inferred signatures. We also provide a new intuitive way to visualize the signatures, analogous to the use of sequence logos to visualize transcription factor binding sites. We illustrate our new method on somatic mutation data from urothelial carcinoma of the upper urinary tract, and a larger dataset from 30 diverse cancer types. The results illustrate several important features of our methods, including the ability of our new visualization tool to clearly highlight the key features of each signature, the improved robustness of signature inferences from small sample sizes, and more detailed inference of signature characteristics such as strand biases and sequence context effects at the base two positions 5' to the mutated site. The overall framework of our work is based on probabilistic models that are closely connected with "mixed-membership models" which are widely used in population genetic admixture analysis, and in machine learning for document clustering. We argue that recognizing these relationships should help improve understanding of mutation signature extraction problems, and suggests ways to further improve the statistical methods. Our methods are implemented in an R package pmsignature (https://github.com/friend1ws/pmsignature) and a web application available at https://friend1ws.shinyapps.io/pmsignature_shiny/.
Recent advances in sequencing technologies have enabled the production of massive amounts of data on somatic mutations from cancer genomes. These data have led to the detection of characteristic patterns of somatic mutations or "mutation signatures" at an unprecedented resolution, with the potential for new insights into the causes and mechanisms of tumorigenesis. Here we present new methods for modelling, identifying and visualizing such mutation signatures. Our methods greatly simplify mutation signature models compared with existing approaches, reducing the number of parameters by orders of magnitude even while increasing the contextual factors (e.g. the number of flanking bases) that are accounted for. This improves both sensitivity and robustness of inferred signatures. We also provide a new intuitive way to visualize the signatures, analogous to the use of sequence logos to visualize transcription factor binding sites. We illustrate our new method on somatic mutation data from urothelial carcinoma of the upper urinary tract, and a larger dataset from 30 diverse cancer types. The results illustrate several important features of our methods, including the ability of our new visualization tool to clearly highlight the key features of each signature, the improved robustness of signature inferences from small sample sizes, and more detailed inference of signature characteristics such as strand biases and sequence context effects at the base two positions 5' to the mutated site. The overall framework of our work is based on probabilistic models that are closely connected with "mixed-membership models" which are widely used in population genetic admixture analysis, and in machine learning for document clustering. We argue that recognizing these relationships should help improve understanding of mutation signature extraction problems, and suggests ways to further improve the statistical methods. Our methods are implemented in an R package pmsignature (https://github.com/friend1ws/pmsignature) and a web application available at https://friend1ws.shinyapps.io/pmsignature_shiny/.Recent advances in sequencing technologies have enabled the production of massive amounts of data on somatic mutations from cancer genomes. These data have led to the detection of characteristic patterns of somatic mutations or "mutation signatures" at an unprecedented resolution, with the potential for new insights into the causes and mechanisms of tumorigenesis. Here we present new methods for modelling, identifying and visualizing such mutation signatures. Our methods greatly simplify mutation signature models compared with existing approaches, reducing the number of parameters by orders of magnitude even while increasing the contextual factors (e.g. the number of flanking bases) that are accounted for. This improves both sensitivity and robustness of inferred signatures. We also provide a new intuitive way to visualize the signatures, analogous to the use of sequence logos to visualize transcription factor binding sites. We illustrate our new method on somatic mutation data from urothelial carcinoma of the upper urinary tract, and a larger dataset from 30 diverse cancer types. The results illustrate several important features of our methods, including the ability of our new visualization tool to clearly highlight the key features of each signature, the improved robustness of signature inferences from small sample sizes, and more detailed inference of signature characteristics such as strand biases and sequence context effects at the base two positions 5' to the mutated site. The overall framework of our work is based on probabilistic models that are closely connected with "mixed-membership models" which are widely used in population genetic admixture analysis, and in machine learning for document clustering. We argue that recognizing these relationships should help improve understanding of mutation signature extraction problems, and suggests ways to further improve the statistical methods. Our methods are implemented in an R package pmsignature (https://github.com/friend1ws/pmsignature) and a web application available at https://friend1ws.shinyapps.io/pmsignature_shiny/.
Recent advances in sequencing technologies have enabled the production of massive amounts of data on somatic mutations from cancer genomes. These data have led to the detection of characteristic patterns of somatic mutations or “mutation signatures” at an unprecedented resolution, with the potential for new insights into the causes and mechanisms of tumorigenesis. Here we present new methods for modelling, identifying and visualizing such mutation signatures. Our methods greatly simplify mutation signature models compared with existing approaches, reducing the number of parameters by orders of magnitude even while increasing the contextual factors (e.g. the number of flanking bases) that are accounted for. This improves both sensitivity and robustness of inferred signatures. We also provide a new intuitive way to visualize the signatures, analogous to the use of sequence logos to visualize transcription factor binding sites. We illustrate our new method on somatic mutation data from urothelial carcinoma of the upper urinary tract, and a larger dataset from 30 diverse cancer types. The results illustrate several important features of our methods, including the ability of our new visualization tool to clearly highlight the key features of each signature, the improved robustness of signature inferences from small sample sizes, and more detailed inference of signature characteristics such as strand biases and sequence context effects at the base two positions 5′ to the mutated site. The overall framework of our work is based on probabilistic models that are closely connected with “mixed-membership models” which are widely used in population genetic admixture analysis, and in machine learning for document clustering. We argue that recognizing these relationships should help improve understanding of mutation signature extraction problems, and suggests ways to further improve the statistical methods. Our methods are implemented in an R package pmsignature (https://github.com/friend1ws/pmsignature) and a web application available at https://friend1ws.shinyapps.io/pmsignature_shiny/. Somatic (non-inherited) mutations are acquired throughout our lives in cells throughout our body. These mutations can be caused, for example, by DNA replication errors or exposure to environmental mutagens such as tobacco smoke. Some of these mutations can lead to cancer. Different cancers, and even different instances of the same cancer, can show different distinctive patterns of somatic mutations. These distinctive patterns have become known as “mutation signatures”. For example, C > A mutations are frequent in lung caners whereas C > T and CC > TT mutations are frequent in skin cancers. Each mutation signature may be associated with a specific kind of carcinogen, such as tobacco smoke or ultraviolet light. Identifying mutation signatures therefore has the potential to identify new carcinogens, and yield new insights into the mechanisms and causes of cancer, In this paper, we introduce new statistical tools for tackling this important problem. These tools provide more robust and interpretable mutation signatures compared to previous approaches, as we demonstrate by applying them to large-scale cancer genomic data.
Audience Academic
Author Shiraishi, Yuichi
Miyano, Satoru
Tremmel, Georg
Stephens, Matthew
AuthorAffiliation University of Oxford, UNITED KINGDOM
1 Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
3 Department of Statistics, University of Chicago, Chicago, Illinois, United States of America
2 Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America
AuthorAffiliation_xml – name: University of Oxford, UNITED KINGDOM
– name: 3 Department of Statistics, University of Chicago, Chicago, Illinois, United States of America
– name: 1 Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
– name: 2 Department of Human Genetics, University of Chicago, Chicago, Illinois, United States of America
Author_xml – sequence: 1
  givenname: Yuichi
  surname: Shiraishi
  fullname: Shiraishi, Yuichi
– sequence: 2
  givenname: Georg
  surname: Tremmel
  fullname: Tremmel, Georg
– sequence: 3
  givenname: Satoru
  surname: Miyano
  fullname: Miyano, Satoru
– sequence: 4
  givenname: Matthew
  surname: Stephens
  fullname: Stephens, Matthew
BackLink https://www.ncbi.nlm.nih.gov/pubmed/26630308$$D View this record in MEDLINE/PubMed
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ContentType Journal Article
Copyright COPYRIGHT 2015 Public Library of Science
2015 Shiraishi et al 2015 Shiraishi et al
2015 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Shiraishi Y, Tremmel G, Miyano S, Stephens M (2015) A Simple Model-Based Approach to Inferring and Visualizing Cancer Mutation Signatures. PLoS Genet 11(12): e1005657. doi:10.1371/journal.pgen.1005657
Copyright_xml – notice: COPYRIGHT 2015 Public Library of Science
– notice: 2015 Shiraishi et al 2015 Shiraishi et al
– notice: 2015 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Shiraishi Y, Tremmel G, Miyano S, Stephens M (2015) A Simple Model-Based Approach to Inferring and Visualizing Cancer Mutation Signatures. PLoS Genet 11(12): e1005657. doi:10.1371/journal.pgen.1005657
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Conceived and designed the experiments: YS MS. Performed the experiments: YS. Analyzed the data: YS MS. Contributed reagents/materials/analysis tools: GT SM. Wrote the paper: YS MS. Designed visualization of mutation signature: GT.
The authors have declared that no competing interests exist.
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PMID 26630308
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Snippet Recent advances in sequencing technologies have enabled the production of massive amounts of data on somatic mutations from cancer genomes. These data have led...
  Recent advances in sequencing technologies have enabled the production of massive amounts of data on somatic mutations from cancer genomes. These data have...
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StartPage e1005657
SubjectTerms Algorithms
Amino Acid Substitution - genetics
Binding sites
Cancer
Carcinoma - genetics
Carcinoma - pathology
Cell growth
Cluster Analysis
Deoxyribonucleic acid
DNA
DNA Mutational Analysis
Epigenomics
Experiments
Gene mutations
Genetic aspects
Genome
Genomes
Humans
Laboratories
Melanoma
Metastasis
Methods
Models, Statistical
Models, Theoretical
Mutation
Mutation - genetics
Neoplasms - genetics
Neoplasms - pathology
Observations
Tobacco smoke
Transcription, Genetic
Visualization
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Title A Simple Model-Based Approach to Inferring and Visualizing Cancer Mutation Signatures
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http://dx.doi.org/10.1371/journal.pgen.1005657
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