Palimpsest: an R package for studying mutational and structural variant signatures along clonal evolution in cancer

Palimpsest: an R package for studying mutational and structural variant signatures along clonal... Abstract Summary Cancer genomes are altered by various mutational processes and, like palimpsests, bear the signatures of these different processes. The Palimpsest R package provides a complete workflow for the characterization and visualization of mutational signatures and their evolution along tumor development. The package covers a wide range of functions for extracting both base substitution and structural variant signatures, inferring the clonality of each alteration and analyzing the evolution of mutational processes between early clonal and late subclonal events. Palimpsest also estimates the probability of each mutation being due to each process to predict the mechanisms at the origin of driver events. Palimpsest is an easy-to-use toolset for reconstructing the natural history of a tumor using whole exome or whole genome sequencing data. Availability and implementation Palimpsest is freely available at www.github.com/FunGEST/Palimpsest. Supplementary information Supplementary data are available at Bioinformatics online. 1 Introduction Mutational signature analysis is a powerful approach to understand the origin of somatic mutations in cancer (Alexandrov et al., 2013). This approach can be extended to any kind of genomic alteration including structural variants (Helleday et al., 2014). Mutational processes may evolve over time, giving different mutational signatures in early clonal and late subclonal mutations (Nik-Zainal et al., 2012; Rubanova et al., 2018). Next-generation sequencing data also allow to reconstruct the timing of copy-number alterations (CNAs) by distinguishing clonal/subclonal events and using the proportion of duplicated mutations to time chromosome duplications (Greenman et al., 2012). Finally, different mutational processes have different propensities to target specific loci depending on the local chromatin state (Polak et al., 2015; Sabarinathan et al., 2016) and sequence context (Letouzé et al., 2017). Understanding how mutational processes evolve during tumorigenesis and alter specific driver genes is critical to better understand the natural history of cancers and eventually predict and influence their clinical behavior. To the best of our knowledge, no comprehensive workflow integrates mutational signature and clonality analyses to reconstruct the natural history of a tumor. In addition, no automated tools for extracting structural variant signatures, timing chromosome duplications and estimating the process at the origin of each mutation are currently available. The Palimpsest R package provides an extensive toolset to explore and visualize the diverse processes generating somatic alterations in a tumor, their evolution along tumorigenesis and their interaction with driver genes. 2 Features of palimpsest Palimpsest takes as input somatic mutations and structural variants (optional), copy-number data and a minimal sample annotation file indicating gender and tumor purity. Figure 1A and Supplementary Figure S1 illustrate a typical Palimpsest analysis, as described step by step below. Fig. 1. View largeDownload slide (A) Workflow of a typical analysis with Palimpsest. (B) Oncogenic timeline of a tumor representing the number of clonal/subclonal mutations, the contribution of mutational processes to each step and the timing of driver mutations (colored according to their most likely causal mutational process) and CNAs Fig. 1. View largeDownload slide (A) Workflow of a typical analysis with Palimpsest. (B) Oncogenic timeline of a tumor representing the number of clonal/subclonal mutations, the contribution of mutational processes to each step and the timing of driver mutations (colored according to their most likely causal mutational process) and CNAs Mutational signature analysis. Palimpsest allows both de novo extraction of novel mutational signatures or quantification of previously described signatures using non-negative matrix factorization (NMF), as implemented in the NMF R package (Gaujoux and Seoighe, 2010). Utilities are provided to visualize signatures, transcriptional strand biases and inter-mutation distance, and to compare signatures using cosine similarity. Structural variant signature analysis. Palimpsest implements an adaptation of the mutational signature analysis framework for structural variants (SVs). SVs are first classified into 38 categories according to the type (deletion, tandem duplication, inversion and interchromosomal translocation) and size of rearrangements (Nik-Zainal et al., 2016). NMF then allows extracting new or known structural variant signatures and their contribution to each tumor genome. Predicting the process at the origin of each individual mutation. Once the mutation catalogue of a tumor has been deconvoluted as the addition of several mutational processes, Palimpsest estimates the probability of each individual mutation being due to each process using simple Bayesian statistics (Letouzé et al., 2017). This key feature, available for both point mutations and structural variants, allows predicting the processes most likely at the origin of driver events in each tumor. Clonality analysis and evolution of mutational signatures. Palimpsest integrates variant allele fraction, tumor purity and local copy number to estimate the proportion of tumor cells harboring each mutation and classify them as clonal or subclonal. Then, the package extracts and compares mutational signatures operative in clonal and subclonal mutations to explore the evolution of mutational processes along tumorigenesis. Timing CNAs. Several tools have been described to differentiate clonal from subclonal CNAs, which can be directly specified in the CNA input file. In addition, Palimpsest will estimate the molecular timing of duplications using the proportion of duplicated/non-duplicated somatic mutations. Oncogenic timelines. Finally, Palimpsest integrates the results of clonality and mutational signature analyses to generate a comprehensive representation of the natural history of the tumor (Fig. 1B). 3 Conclusions Unraveling what mutational processes generate driver mutations and fuel the initiation and progression of tumor clones is crucial to better understand the natural history of cancers and optimize personalized patient care. Palimpsest integrates a broad range of functions within a single convenient workflow to provide a complete picture of tumorigenesis. The minimum basic input data make the package easy-to-use in any cancer genomic study downstream classical variant calling and copy number analyses. Acknowledgements We thank the CIT program from the French Ligue Nationale Contre le Cancer for providing useful R codes (cit.x functions). Funding This work was supported by INSERM (“Cancer et environnement” & HTE program), cancéropôle Ile-de-France (exhauTrans project), Région Ile-de-France, BPI France (ICE project), CARPEM and ICGC. The group is supported by the Ligue Nationale contre le Cancer (Equipe Labellisée), Labex OncoImmunology Investissement d’Avenir and Fondation Mérieux. Conflict of Interest: none declared. References Alexandrov L.B. et al. ( 2013 ) Signatures of mutational processes in human cancer . Nature , 500 , 415 – 421 . Google Scholar Crossref Search ADS PubMed Gaujoux R. , Seoighe C. ( 2010 ) A flexible R package for nonnegative matrix factorization . BMC Bioinformatics , 11 , 367. Google Scholar Crossref Search ADS PubMed Greenman C.D. et al. ( 2012 ) Estimation of rearrangement phylogeny for cancer genomes . Genome Res ., 22 , 346 – 361 . Google Scholar Crossref Search ADS PubMed Helleday T. et al. ( 2014 ) Mechanisms underlying mutational signatures in human cancers . Nat. Rev. Genet ., 15 , 585 – 598 . Google Scholar Crossref Search ADS PubMed Letouzé E. et al. ( 2017 ) Mutational signatures reveal the dynamic interplay of risk factors and cellular processes during liver tumorigenesis . Nat. Commun ., 8 , 1315 . Google Scholar Crossref Search ADS PubMed Nik-Zainal S. et al. ( 2012 ) The life history of 21 breast cancers . Cell , 149 , 994 – 1007 . Google Scholar Crossref Search ADS PubMed Nik-Zainal S. et al. ( 2016 ) Landscape of somatic mutations in 560 breast cancer whole-genome sequences . Nature , 534 , 47 – 54 . Google Scholar Crossref Search ADS PubMed Polak P. et al. ( 2015 ) Cell-of-origin chromatin organization shapes the mutational landscape of cancer . Nature , 518 , 360 – 364 . Google Scholar Crossref Search ADS PubMed Rubanova Y. et al. ( 2018 ) TrackSig: reconstructing evolutionary trajectories of mutation signature exposure. bioRxiv, 260471. Sabarinathan R. et al. ( 2016 ) Nucleotide excision repair is impaired by binding of transcription factors to DNA . Nature , 532 , 264 – 267 . Google Scholar Crossref Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Bioinformatics Oxford University Press

Palimpsest: an R package for studying mutational and structural variant signatures along clonal evolution in cancer

Loading next page...
 
/lp/ou_press/palimpsest-an-r-package-for-studying-mutational-and-structural-variant-WvKWEcxzmw
Publisher
Oxford University Press
Copyright
© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
ISSN
1367-4803
eISSN
1460-2059
D.O.I.
10.1093/bioinformatics/bty388
Publisher site
See Article on Publisher Site

Abstract

Abstract Summary Cancer genomes are altered by various mutational processes and, like palimpsests, bear the signatures of these different processes. The Palimpsest R package provides a complete workflow for the characterization and visualization of mutational signatures and their evolution along tumor development. The package covers a wide range of functions for extracting both base substitution and structural variant signatures, inferring the clonality of each alteration and analyzing the evolution of mutational processes between early clonal and late subclonal events. Palimpsest also estimates the probability of each mutation being due to each process to predict the mechanisms at the origin of driver events. Palimpsest is an easy-to-use toolset for reconstructing the natural history of a tumor using whole exome or whole genome sequencing data. Availability and implementation Palimpsest is freely available at www.github.com/FunGEST/Palimpsest. Supplementary information Supplementary data are available at Bioinformatics online. 1 Introduction Mutational signature analysis is a powerful approach to understand the origin of somatic mutations in cancer (Alexandrov et al., 2013). This approach can be extended to any kind of genomic alteration including structural variants (Helleday et al., 2014). Mutational processes may evolve over time, giving different mutational signatures in early clonal and late subclonal mutations (Nik-Zainal et al., 2012; Rubanova et al., 2018). Next-generation sequencing data also allow to reconstruct the timing of copy-number alterations (CNAs) by distinguishing clonal/subclonal events and using the proportion of duplicated mutations to time chromosome duplications (Greenman et al., 2012). Finally, different mutational processes have different propensities to target specific loci depending on the local chromatin state (Polak et al., 2015; Sabarinathan et al., 2016) and sequence context (Letouzé et al., 2017). Understanding how mutational processes evolve during tumorigenesis and alter specific driver genes is critical to better understand the natural history of cancers and eventually predict and influence their clinical behavior. To the best of our knowledge, no comprehensive workflow integrates mutational signature and clonality analyses to reconstruct the natural history of a tumor. In addition, no automated tools for extracting structural variant signatures, timing chromosome duplications and estimating the process at the origin of each mutation are currently available. The Palimpsest R package provides an extensive toolset to explore and visualize the diverse processes generating somatic alterations in a tumor, their evolution along tumorigenesis and their interaction with driver genes. 2 Features of palimpsest Palimpsest takes as input somatic mutations and structural variants (optional), copy-number data and a minimal sample annotation file indicating gender and tumor purity. Figure 1A and Supplementary Figure S1 illustrate a typical Palimpsest analysis, as described step by step below. Fig. 1. View largeDownload slide (A) Workflow of a typical analysis with Palimpsest. (B) Oncogenic timeline of a tumor representing the number of clonal/subclonal mutations, the contribution of mutational processes to each step and the timing of driver mutations (colored according to their most likely causal mutational process) and CNAs Fig. 1. View largeDownload slide (A) Workflow of a typical analysis with Palimpsest. (B) Oncogenic timeline of a tumor representing the number of clonal/subclonal mutations, the contribution of mutational processes to each step and the timing of driver mutations (colored according to their most likely causal mutational process) and CNAs Mutational signature analysis. Palimpsest allows both de novo extraction of novel mutational signatures or quantification of previously described signatures using non-negative matrix factorization (NMF), as implemented in the NMF R package (Gaujoux and Seoighe, 2010). Utilities are provided to visualize signatures, transcriptional strand biases and inter-mutation distance, and to compare signatures using cosine similarity. Structural variant signature analysis. Palimpsest implements an adaptation of the mutational signature analysis framework for structural variants (SVs). SVs are first classified into 38 categories according to the type (deletion, tandem duplication, inversion and interchromosomal translocation) and size of rearrangements (Nik-Zainal et al., 2016). NMF then allows extracting new or known structural variant signatures and their contribution to each tumor genome. Predicting the process at the origin of each individual mutation. Once the mutation catalogue of a tumor has been deconvoluted as the addition of several mutational processes, Palimpsest estimates the probability of each individual mutation being due to each process using simple Bayesian statistics (Letouzé et al., 2017). This key feature, available for both point mutations and structural variants, allows predicting the processes most likely at the origin of driver events in each tumor. Clonality analysis and evolution of mutational signatures. Palimpsest integrates variant allele fraction, tumor purity and local copy number to estimate the proportion of tumor cells harboring each mutation and classify them as clonal or subclonal. Then, the package extracts and compares mutational signatures operative in clonal and subclonal mutations to explore the evolution of mutational processes along tumorigenesis. Timing CNAs. Several tools have been described to differentiate clonal from subclonal CNAs, which can be directly specified in the CNA input file. In addition, Palimpsest will estimate the molecular timing of duplications using the proportion of duplicated/non-duplicated somatic mutations. Oncogenic timelines. Finally, Palimpsest integrates the results of clonality and mutational signature analyses to generate a comprehensive representation of the natural history of the tumor (Fig. 1B). 3 Conclusions Unraveling what mutational processes generate driver mutations and fuel the initiation and progression of tumor clones is crucial to better understand the natural history of cancers and optimize personalized patient care. Palimpsest integrates a broad range of functions within a single convenient workflow to provide a complete picture of tumorigenesis. The minimum basic input data make the package easy-to-use in any cancer genomic study downstream classical variant calling and copy number analyses. Acknowledgements We thank the CIT program from the French Ligue Nationale Contre le Cancer for providing useful R codes (cit.x functions). Funding This work was supported by INSERM (“Cancer et environnement” & HTE program), cancéropôle Ile-de-France (exhauTrans project), Région Ile-de-France, BPI France (ICE project), CARPEM and ICGC. The group is supported by the Ligue Nationale contre le Cancer (Equipe Labellisée), Labex OncoImmunology Investissement d’Avenir and Fondation Mérieux. Conflict of Interest: none declared. References Alexandrov L.B. et al. ( 2013 ) Signatures of mutational processes in human cancer . Nature , 500 , 415 – 421 . Google Scholar Crossref Search ADS PubMed Gaujoux R. , Seoighe C. ( 2010 ) A flexible R package for nonnegative matrix factorization . BMC Bioinformatics , 11 , 367. Google Scholar Crossref Search ADS PubMed Greenman C.D. et al. ( 2012 ) Estimation of rearrangement phylogeny for cancer genomes . Genome Res ., 22 , 346 – 361 . Google Scholar Crossref Search ADS PubMed Helleday T. et al. ( 2014 ) Mechanisms underlying mutational signatures in human cancers . Nat. Rev. Genet ., 15 , 585 – 598 . Google Scholar Crossref Search ADS PubMed Letouzé E. et al. ( 2017 ) Mutational signatures reveal the dynamic interplay of risk factors and cellular processes during liver tumorigenesis . Nat. Commun ., 8 , 1315 . Google Scholar Crossref Search ADS PubMed Nik-Zainal S. et al. ( 2012 ) The life history of 21 breast cancers . Cell , 149 , 994 – 1007 . Google Scholar Crossref Search ADS PubMed Nik-Zainal S. et al. ( 2016 ) Landscape of somatic mutations in 560 breast cancer whole-genome sequences . Nature , 534 , 47 – 54 . Google Scholar Crossref Search ADS PubMed Polak P. et al. ( 2015 ) Cell-of-origin chromatin organization shapes the mutational landscape of cancer . Nature , 518 , 360 – 364 . Google Scholar Crossref Search ADS PubMed Rubanova Y. et al. ( 2018 ) TrackSig: reconstructing evolutionary trajectories of mutation signature exposure. bioRxiv, 260471. Sabarinathan R. et al. ( 2016 ) Nucleotide excision repair is impaired by binding of transcription factors to DNA . Nature , 532 , 264 – 267 . Google Scholar Crossref Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Journal

BioinformaticsOxford University Press

Published: Oct 1, 2018

References

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off