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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...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2017
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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. |
format | Online Article Text |
id | pubmed-5871833 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
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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