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Resolving the phylogenetic origin of glioblastoma via multifocal genomic analysis of pre-treatment and treatment-resistant autopsy specimens

Glioblastomas are malignant neoplasms composed of diverse cell populations. This intratumoral diversity has an underlying architecture, with a hierarchical relationship through clonal evolution from a common ancestor. Therapies are limited by emergence of resistant subclones from this phylogenetic r...

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Autores principales: Brastianos, Priscilla K., Nayyar, Naema, Rosebrock, Daniel, Leshchiner, Ignaty, Gill, Corey M., Livitz, Dimitri, Bertalan, Mia S., D’Andrea, Megan, Hoang, Kaitlin, Aquilanti, Elisa, Chukwueke, Ugonma N., Kaneb, Andrew, Chi, Andrew, Plotkin, Scott, Gerstner, Elizabeth R., Frosch, Mathew P., Suva, Mario L., Cahill, Daniel P., Getz, Gad, Batchelor, Tracy T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5871833/
https://www.ncbi.nlm.nih.gov/pubmed/29872714
http://dx.doi.org/10.1038/s41698-017-0035-9
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author Brastianos, Priscilla K.
Nayyar, Naema
Rosebrock, Daniel
Leshchiner, Ignaty
Gill, Corey M.
Livitz, Dimitri
Bertalan, Mia S.
D’Andrea, Megan
Hoang, Kaitlin
Aquilanti, Elisa
Chukwueke, Ugonma N.
Kaneb, Andrew
Chi, Andrew
Plotkin, Scott
Gerstner, Elizabeth R.
Frosch, Mathew P.
Suva, Mario L.
Cahill, Daniel P.
Getz, Gad
Batchelor, Tracy T.
author_facet Brastianos, Priscilla K.
Nayyar, Naema
Rosebrock, Daniel
Leshchiner, Ignaty
Gill, Corey M.
Livitz, Dimitri
Bertalan, Mia S.
D’Andrea, Megan
Hoang, Kaitlin
Aquilanti, Elisa
Chukwueke, Ugonma N.
Kaneb, Andrew
Chi, Andrew
Plotkin, Scott
Gerstner, Elizabeth R.
Frosch, Mathew P.
Suva, Mario L.
Cahill, Daniel P.
Getz, Gad
Batchelor, Tracy T.
author_sort Brastianos, Priscilla K.
collection PubMed
description Glioblastomas are malignant neoplasms composed of diverse cell populations. This intratumoral diversity has an underlying architecture, with a hierarchical relationship through clonal evolution from a common ancestor. Therapies are limited by emergence of resistant subclones from this phylogenetic reservoir. To characterize this clonal ancestral origin of recurrent tumors, we determined phylogenetic relationships using whole exome sequencing of pre-treatment IDH1/2 wild-type glioblastoma specimens, matched to post-treatment autopsy samples (n = 9) and metastatic extracranial post-treatment autopsy samples (n = 3). We identified “truncal” genetic events common to the evolutionary ancestry of the initial specimen and later recurrences, thereby inferring the identity of the precursor cell population. Mutations were identified in a subset of cases in known glioblastoma genes such as NF1(n = 3), TP53(n = 4) and EGFR(n = 5). However, by phylogenetic analysis, there were no protein-coding mutations as recurrent truncal events across the majority of cases. In contrast, whole copy-loss of chromosome 10 (12 of 12 cases), copy-loss of chromosome 9p21 (11 of 12 cases) and copy-gain in chromosome 7 (10 of 12 cases) were identified as shared events in the majority of cases. Strikingly, mutations in the TERT promoter were also identified as shared events in all evaluated pairs (9 of 9). Thus, we define four truncal non-coding genomic alterations that represent early genomic events in gliomagenesis, that identify the persistent cellular reservoir from which glioblastoma recurrences emerge. Therapies to target these key early genomic events are needed. These findings offer an evolutionary explanation for why precision therapies that target protein-coding mutations lack efficacy in GBM.
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spelling pubmed-58718332018-06-05 Resolving the phylogenetic origin of glioblastoma via multifocal genomic analysis of pre-treatment and treatment-resistant autopsy specimens Brastianos, Priscilla K. Nayyar, Naema Rosebrock, Daniel Leshchiner, Ignaty Gill, Corey M. Livitz, Dimitri Bertalan, Mia S. D’Andrea, Megan Hoang, Kaitlin Aquilanti, Elisa Chukwueke, Ugonma N. Kaneb, Andrew Chi, Andrew Plotkin, Scott Gerstner, Elizabeth R. Frosch, Mathew P. Suva, Mario L. Cahill, Daniel P. Getz, Gad Batchelor, Tracy T. NPJ Precis Oncol Article Glioblastomas are malignant neoplasms composed of diverse cell populations. This intratumoral diversity has an underlying architecture, with a hierarchical relationship through clonal evolution from a common ancestor. Therapies are limited by emergence of resistant subclones from this phylogenetic reservoir. To characterize this clonal ancestral origin of recurrent tumors, we determined phylogenetic relationships using whole exome sequencing of pre-treatment IDH1/2 wild-type glioblastoma specimens, matched to post-treatment autopsy samples (n = 9) and metastatic extracranial post-treatment autopsy samples (n = 3). We identified “truncal” genetic events common to the evolutionary ancestry of the initial specimen and later recurrences, thereby inferring the identity of the precursor cell population. Mutations were identified in a subset of cases in known glioblastoma genes such as NF1(n = 3), TP53(n = 4) and EGFR(n = 5). However, by phylogenetic analysis, there were no protein-coding mutations as recurrent truncal events across the majority of cases. In contrast, whole copy-loss of chromosome 10 (12 of 12 cases), copy-loss of chromosome 9p21 (11 of 12 cases) and copy-gain in chromosome 7 (10 of 12 cases) were identified as shared events in the majority of cases. Strikingly, mutations in the TERT promoter were also identified as shared events in all evaluated pairs (9 of 9). Thus, we define four truncal non-coding genomic alterations that represent early genomic events in gliomagenesis, that identify the persistent cellular reservoir from which glioblastoma recurrences emerge. Therapies to target these key early genomic events are needed. These findings offer an evolutionary explanation for why precision therapies that target protein-coding mutations lack efficacy in GBM. Nature Publishing Group UK 2017-09-18 /pmc/articles/PMC5871833/ /pubmed/29872714 http://dx.doi.org/10.1038/s41698-017-0035-9 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Brastianos, Priscilla K.
Nayyar, Naema
Rosebrock, Daniel
Leshchiner, Ignaty
Gill, Corey M.
Livitz, Dimitri
Bertalan, Mia S.
D’Andrea, Megan
Hoang, Kaitlin
Aquilanti, Elisa
Chukwueke, Ugonma N.
Kaneb, Andrew
Chi, Andrew
Plotkin, Scott
Gerstner, Elizabeth R.
Frosch, Mathew P.
Suva, Mario L.
Cahill, Daniel P.
Getz, Gad
Batchelor, Tracy T.
Resolving the phylogenetic origin of glioblastoma via multifocal genomic analysis of pre-treatment and treatment-resistant autopsy specimens
title Resolving the phylogenetic origin of glioblastoma via multifocal genomic analysis of pre-treatment and treatment-resistant autopsy specimens
title_full Resolving the phylogenetic origin of glioblastoma via multifocal genomic analysis of pre-treatment and treatment-resistant autopsy specimens
title_fullStr Resolving the phylogenetic origin of glioblastoma via multifocal genomic analysis of pre-treatment and treatment-resistant autopsy specimens
title_full_unstemmed Resolving the phylogenetic origin of glioblastoma via multifocal genomic analysis of pre-treatment and treatment-resistant autopsy specimens
title_short Resolving the phylogenetic origin of glioblastoma via multifocal genomic analysis of pre-treatment and treatment-resistant autopsy specimens
title_sort resolving the phylogenetic origin of glioblastoma via multifocal genomic analysis of pre-treatment and treatment-resistant autopsy specimens
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5871833/
https://www.ncbi.nlm.nih.gov/pubmed/29872714
http://dx.doi.org/10.1038/s41698-017-0035-9
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