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Comprehensive analysis of cancer breakpoints reveals signatures of genetic and epigenetic contribution to cancer genome rearrangements

Understanding mechanisms of cancer breakpoint mutagenesis is a difficult task and predictive models of cancer breakpoint formation have to this time failed to achieve even moderate predictive power. Here we take advantage of a machine learning approach that can gather important features from big dat...

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Autores principales: Cheloshkina, Kseniia, Poptsova, Maria
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951985/
https://www.ncbi.nlm.nih.gov/pubmed/33647036
http://dx.doi.org/10.1371/journal.pcbi.1008749
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author Cheloshkina, Kseniia
Poptsova, Maria
author_facet Cheloshkina, Kseniia
Poptsova, Maria
author_sort Cheloshkina, Kseniia
collection PubMed
description Understanding mechanisms of cancer breakpoint mutagenesis is a difficult task and predictive models of cancer breakpoint formation have to this time failed to achieve even moderate predictive power. Here we take advantage of a machine learning approach that can gather important features from big data and quantify contribution of different factors. We performed comprehensive analysis of almost 630,000 cancer breakpoints and quantified the contribution of genomic and epigenomic features–non-B DNA structures, chromatin organization, transcription factor binding sites and epigenetic markers. The results showed that transcription and formation of non-B DNA structures are two major processes responsible for cancer genome fragility. Epigenetic factors, such as chromatin organization in TADs, open/closed regions, DNA methylation, histone marks are less informative but do make their contribution. As a general trend, individual features inside the groups show a relatively high contribution of G-quadruplexes and repeats and CTCF, GABPA, RXRA, SP1, MAX and NR2F2 transcription factors. Overall, the cancer breakpoint landscape can be represented by well-predicted hotspots and poorly predicted individual breakpoints scattered across genomes. We demonstrated that hotspot mutagenesis has genomic and epigenomic factors, and not all individual cancer breakpoints are just random noise but have a definite mutation signature. Besides we found a long-range action of some features on breakpoint mutagenesis. Combining omics data, cancer-specific individual feature importance and adding the distant to local features, predictive models for cancer breakpoint formation achieved 70–90% ROC AUC for different cancer types; however precision remained low at 2% and the recall did not exceed 50%. On the one hand, the power of models strongly correlates with the size of available cancer breakpoint and epigenomic data, and on the other hand finding strong determinants of cancer breakpoint formation still remains a challenge. The strength of predictive signals of each group and of each feature inside a group can be converted into cancer-specific breakpoint mutation signatures. Overall our results add to the understanding of cancer genome rearrangement processes.
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spelling pubmed-79519852021-03-22 Comprehensive analysis of cancer breakpoints reveals signatures of genetic and epigenetic contribution to cancer genome rearrangements Cheloshkina, Kseniia Poptsova, Maria PLoS Comput Biol Research Article Understanding mechanisms of cancer breakpoint mutagenesis is a difficult task and predictive models of cancer breakpoint formation have to this time failed to achieve even moderate predictive power. Here we take advantage of a machine learning approach that can gather important features from big data and quantify contribution of different factors. We performed comprehensive analysis of almost 630,000 cancer breakpoints and quantified the contribution of genomic and epigenomic features–non-B DNA structures, chromatin organization, transcription factor binding sites and epigenetic markers. The results showed that transcription and formation of non-B DNA structures are two major processes responsible for cancer genome fragility. Epigenetic factors, such as chromatin organization in TADs, open/closed regions, DNA methylation, histone marks are less informative but do make their contribution. As a general trend, individual features inside the groups show a relatively high contribution of G-quadruplexes and repeats and CTCF, GABPA, RXRA, SP1, MAX and NR2F2 transcription factors. Overall, the cancer breakpoint landscape can be represented by well-predicted hotspots and poorly predicted individual breakpoints scattered across genomes. We demonstrated that hotspot mutagenesis has genomic and epigenomic factors, and not all individual cancer breakpoints are just random noise but have a definite mutation signature. Besides we found a long-range action of some features on breakpoint mutagenesis. Combining omics data, cancer-specific individual feature importance and adding the distant to local features, predictive models for cancer breakpoint formation achieved 70–90% ROC AUC for different cancer types; however precision remained low at 2% and the recall did not exceed 50%. On the one hand, the power of models strongly correlates with the size of available cancer breakpoint and epigenomic data, and on the other hand finding strong determinants of cancer breakpoint formation still remains a challenge. The strength of predictive signals of each group and of each feature inside a group can be converted into cancer-specific breakpoint mutation signatures. Overall our results add to the understanding of cancer genome rearrangement processes. Public Library of Science 2021-03-01 /pmc/articles/PMC7951985/ /pubmed/33647036 http://dx.doi.org/10.1371/journal.pcbi.1008749 Text en © 2021 Cheloshkina, Poptsova http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Cheloshkina, Kseniia
Poptsova, Maria
Comprehensive analysis of cancer breakpoints reveals signatures of genetic and epigenetic contribution to cancer genome rearrangements
title Comprehensive analysis of cancer breakpoints reveals signatures of genetic and epigenetic contribution to cancer genome rearrangements
title_full Comprehensive analysis of cancer breakpoints reveals signatures of genetic and epigenetic contribution to cancer genome rearrangements
title_fullStr Comprehensive analysis of cancer breakpoints reveals signatures of genetic and epigenetic contribution to cancer genome rearrangements
title_full_unstemmed Comprehensive analysis of cancer breakpoints reveals signatures of genetic and epigenetic contribution to cancer genome rearrangements
title_short Comprehensive analysis of cancer breakpoints reveals signatures of genetic and epigenetic contribution to cancer genome rearrangements
title_sort comprehensive analysis of cancer breakpoints reveals signatures of genetic and epigenetic contribution to cancer genome rearrangements
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951985/
https://www.ncbi.nlm.nih.gov/pubmed/33647036
http://dx.doi.org/10.1371/journal.pcbi.1008749
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