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Single-cell sequencing data reveal widespread recurrence and loss of mutational hits in the life histories of tumors

Intra-tumor heterogeneity poses substantial challenges for cancer treatment. A tumor's composition can be deduced by reconstructing its mutational history. Central to current approaches is the infinite sites assumption that every genomic position can only mutate once over the lifetime of a tumo...

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Detalles Bibliográficos
Autores principales: Kuipers, Jack, Jahn, Katharina, Raphael, Benjamin J., Beerenwinkel, Niko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5668945/
https://www.ncbi.nlm.nih.gov/pubmed/29030470
http://dx.doi.org/10.1101/gr.220707.117
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author Kuipers, Jack
Jahn, Katharina
Raphael, Benjamin J.
Beerenwinkel, Niko
author_facet Kuipers, Jack
Jahn, Katharina
Raphael, Benjamin J.
Beerenwinkel, Niko
author_sort Kuipers, Jack
collection PubMed
description Intra-tumor heterogeneity poses substantial challenges for cancer treatment. A tumor's composition can be deduced by reconstructing its mutational history. Central to current approaches is the infinite sites assumption that every genomic position can only mutate once over the lifetime of a tumor. The validity of this assumption has never been quantitatively assessed. We developed a rigorous statistical framework to test the infinite sites assumption with single-cell sequencing data. Our framework accounts for the high noise and contamination present in such data. We found strong evidence for the same genomic position being mutationally affected multiple times in individual tumors for 11 of 12 single-cell sequencing data sets from a variety of human cancers. Seven cases involved the loss of earlier mutations, five of which occurred at sites unaffected by large-scale genomic deletions. Four cases exhibited a parallel mutation, potentially indicating convergent evolution at the base pair level. Our results refute the general validity of the infinite sites assumption and indicate that more complex models are needed to adequately quantify intra-tumor heterogeneity for more effective cancer treatment.
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spelling pubmed-56689452018-05-01 Single-cell sequencing data reveal widespread recurrence and loss of mutational hits in the life histories of tumors Kuipers, Jack Jahn, Katharina Raphael, Benjamin J. Beerenwinkel, Niko Genome Res Method Intra-tumor heterogeneity poses substantial challenges for cancer treatment. A tumor's composition can be deduced by reconstructing its mutational history. Central to current approaches is the infinite sites assumption that every genomic position can only mutate once over the lifetime of a tumor. The validity of this assumption has never been quantitatively assessed. We developed a rigorous statistical framework to test the infinite sites assumption with single-cell sequencing data. Our framework accounts for the high noise and contamination present in such data. We found strong evidence for the same genomic position being mutationally affected multiple times in individual tumors for 11 of 12 single-cell sequencing data sets from a variety of human cancers. Seven cases involved the loss of earlier mutations, five of which occurred at sites unaffected by large-scale genomic deletions. Four cases exhibited a parallel mutation, potentially indicating convergent evolution at the base pair level. Our results refute the general validity of the infinite sites assumption and indicate that more complex models are needed to adequately quantify intra-tumor heterogeneity for more effective cancer treatment. Cold Spring Harbor Laboratory Press 2017-11 /pmc/articles/PMC5668945/ /pubmed/29030470 http://dx.doi.org/10.1101/gr.220707.117 Text en © 2017 Kuipers et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Method
Kuipers, Jack
Jahn, Katharina
Raphael, Benjamin J.
Beerenwinkel, Niko
Single-cell sequencing data reveal widespread recurrence and loss of mutational hits in the life histories of tumors
title Single-cell sequencing data reveal widespread recurrence and loss of mutational hits in the life histories of tumors
title_full Single-cell sequencing data reveal widespread recurrence and loss of mutational hits in the life histories of tumors
title_fullStr Single-cell sequencing data reveal widespread recurrence and loss of mutational hits in the life histories of tumors
title_full_unstemmed Single-cell sequencing data reveal widespread recurrence and loss of mutational hits in the life histories of tumors
title_short Single-cell sequencing data reveal widespread recurrence and loss of mutational hits in the life histories of tumors
title_sort single-cell sequencing data reveal widespread recurrence and loss of mutational hits in the life histories of tumors
topic Method
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5668945/
https://www.ncbi.nlm.nih.gov/pubmed/29030470
http://dx.doi.org/10.1101/gr.220707.117
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