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Criticality in tumor evolution and clinical outcome

How mutation and selection determine the fitness landscape of tumors and hence clinical outcome is an open fundamental question in cancer biology, crucial for the assessment of therapeutic strategies and resistance to treatment. Here we explore the mutation-selection phase diagram of 6,721 tumors re...

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Autores principales: Persi, Erez, Wolf, Yuri I., Leiserson, Mark D. M., Koonin, Eugene V., Ruppin, Eytan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6255199/
https://www.ncbi.nlm.nih.gov/pubmed/30404913
http://dx.doi.org/10.1073/pnas.1807256115
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author Persi, Erez
Wolf, Yuri I.
Leiserson, Mark D. M.
Koonin, Eugene V.
Ruppin, Eytan
author_facet Persi, Erez
Wolf, Yuri I.
Leiserson, Mark D. M.
Koonin, Eugene V.
Ruppin, Eytan
author_sort Persi, Erez
collection PubMed
description How mutation and selection determine the fitness landscape of tumors and hence clinical outcome is an open fundamental question in cancer biology, crucial for the assessment of therapeutic strategies and resistance to treatment. Here we explore the mutation-selection phase diagram of 6,721 tumors representing 23 cancer types by quantifying the overall somatic point mutation load (ML) and selection (dN/dS) in the entire proteome of each tumor. We show that ML strongly correlates with patient survival, revealing two opposing regimes around a critical point. In low-ML cancers, a high number of mutations indicates poor prognosis, whereas high-ML cancers show the opposite trend, presumably due to mutational meltdown. Although the majority of cancers evolve near neutrality, deviations are observed at extreme MLs. Melanoma, with the highest ML, evolves under purifying selection, whereas in low-ML cancers, signatures of positive selection are observed, demonstrating how selection affects tumor fitness. Moreover, different cancers occupy specific positions on the ML–dN/dS plane, revealing a diversity of evolutionary trajectories. These results support and expand the theory of tumor evolution and its nonlinear effects on survival.
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spelling pubmed-62551992018-11-30 Criticality in tumor evolution and clinical outcome Persi, Erez Wolf, Yuri I. Leiserson, Mark D. M. Koonin, Eugene V. Ruppin, Eytan Proc Natl Acad Sci U S A PNAS Plus How mutation and selection determine the fitness landscape of tumors and hence clinical outcome is an open fundamental question in cancer biology, crucial for the assessment of therapeutic strategies and resistance to treatment. Here we explore the mutation-selection phase diagram of 6,721 tumors representing 23 cancer types by quantifying the overall somatic point mutation load (ML) and selection (dN/dS) in the entire proteome of each tumor. We show that ML strongly correlates with patient survival, revealing two opposing regimes around a critical point. In low-ML cancers, a high number of mutations indicates poor prognosis, whereas high-ML cancers show the opposite trend, presumably due to mutational meltdown. Although the majority of cancers evolve near neutrality, deviations are observed at extreme MLs. Melanoma, with the highest ML, evolves under purifying selection, whereas in low-ML cancers, signatures of positive selection are observed, demonstrating how selection affects tumor fitness. Moreover, different cancers occupy specific positions on the ML–dN/dS plane, revealing a diversity of evolutionary trajectories. These results support and expand the theory of tumor evolution and its nonlinear effects on survival. National Academy of Sciences 2018-11-20 2018-11-07 /pmc/articles/PMC6255199/ /pubmed/30404913 http://dx.doi.org/10.1073/pnas.1807256115 Text en Copyright © 2018 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle PNAS Plus
Persi, Erez
Wolf, Yuri I.
Leiserson, Mark D. M.
Koonin, Eugene V.
Ruppin, Eytan
Criticality in tumor evolution and clinical outcome
title Criticality in tumor evolution and clinical outcome
title_full Criticality in tumor evolution and clinical outcome
title_fullStr Criticality in tumor evolution and clinical outcome
title_full_unstemmed Criticality in tumor evolution and clinical outcome
title_short Criticality in tumor evolution and clinical outcome
title_sort criticality in tumor evolution and clinical outcome
topic PNAS Plus
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6255199/
https://www.ncbi.nlm.nih.gov/pubmed/30404913
http://dx.doi.org/10.1073/pnas.1807256115
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