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Somatic chromosomal engineering identifies BCAN-NTRK1 as a potent glioma driver and therapeutic target
The widespread application of high-throughput sequencing methods is resulting in the identification of a rapidly growing number of novel gene fusions caused by tumour-specific chromosomal rearrangements, whose oncogenic potential remains unknown. Here we describe a strategy that builds upon recent a...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5508201/ https://www.ncbi.nlm.nih.gov/pubmed/28695888 http://dx.doi.org/10.1038/ncomms15987 |
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author | Cook, Peter J. Thomas, Rozario Kannan, Ram de Leon, Esther Sanchez Drilon, Alexander Rosenblum, Marc K. Scaltriti, Maurizio Benezra, Robert Ventura, Andrea |
author_facet | Cook, Peter J. Thomas, Rozario Kannan, Ram de Leon, Esther Sanchez Drilon, Alexander Rosenblum, Marc K. Scaltriti, Maurizio Benezra, Robert Ventura, Andrea |
author_sort | Cook, Peter J. |
collection | PubMed |
description | The widespread application of high-throughput sequencing methods is resulting in the identification of a rapidly growing number of novel gene fusions caused by tumour-specific chromosomal rearrangements, whose oncogenic potential remains unknown. Here we describe a strategy that builds upon recent advances in genome editing and combines ex vivo and in vivo chromosomal engineering to rapidly and effectively interrogate the oncogenic potential of genomic rearrangements identified in human brain cancers. We show that one such rearrangement, an microdeletion resulting in a fusion between Brevican (BCAN) and Neurotrophic Receptor Tyrosine Kinase 1 (NTRK1), is a potent oncogenic driver of high-grade gliomas and confers sensitivity to the experimental TRK inhibitor entrectinib. This work demonstrates that BCAN-NTRK1 is a bona fide human glioma driver and describes a general strategy to define the oncogenic potential of novel glioma-associated genomic rearrangements and to generate accurate preclinical models of this lethal human cancer. |
format | Online Article Text |
id | pubmed-5508201 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-55082012017-07-17 Somatic chromosomal engineering identifies BCAN-NTRK1 as a potent glioma driver and therapeutic target Cook, Peter J. Thomas, Rozario Kannan, Ram de Leon, Esther Sanchez Drilon, Alexander Rosenblum, Marc K. Scaltriti, Maurizio Benezra, Robert Ventura, Andrea Nat Commun Article The widespread application of high-throughput sequencing methods is resulting in the identification of a rapidly growing number of novel gene fusions caused by tumour-specific chromosomal rearrangements, whose oncogenic potential remains unknown. Here we describe a strategy that builds upon recent advances in genome editing and combines ex vivo and in vivo chromosomal engineering to rapidly and effectively interrogate the oncogenic potential of genomic rearrangements identified in human brain cancers. We show that one such rearrangement, an microdeletion resulting in a fusion between Brevican (BCAN) and Neurotrophic Receptor Tyrosine Kinase 1 (NTRK1), is a potent oncogenic driver of high-grade gliomas and confers sensitivity to the experimental TRK inhibitor entrectinib. This work demonstrates that BCAN-NTRK1 is a bona fide human glioma driver and describes a general strategy to define the oncogenic potential of novel glioma-associated genomic rearrangements and to generate accurate preclinical models of this lethal human cancer. Nature Publishing Group 2017-07-11 /pmc/articles/PMC5508201/ /pubmed/28695888 http://dx.doi.org/10.1038/ncomms15987 Text en Copyright © 2017, The Author(s) http://creativecommons.org/licenses/by/4.0/ 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 Cook, Peter J. Thomas, Rozario Kannan, Ram de Leon, Esther Sanchez Drilon, Alexander Rosenblum, Marc K. Scaltriti, Maurizio Benezra, Robert Ventura, Andrea Somatic chromosomal engineering identifies BCAN-NTRK1 as a potent glioma driver and therapeutic target |
title | Somatic chromosomal engineering identifies BCAN-NTRK1 as a potent glioma driver and therapeutic target |
title_full | Somatic chromosomal engineering identifies BCAN-NTRK1 as a potent glioma driver and therapeutic target |
title_fullStr | Somatic chromosomal engineering identifies BCAN-NTRK1 as a potent glioma driver and therapeutic target |
title_full_unstemmed | Somatic chromosomal engineering identifies BCAN-NTRK1 as a potent glioma driver and therapeutic target |
title_short | Somatic chromosomal engineering identifies BCAN-NTRK1 as a potent glioma driver and therapeutic target |
title_sort | somatic chromosomal engineering identifies bcan-ntrk1 as a potent glioma driver and therapeutic target |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5508201/ https://www.ncbi.nlm.nih.gov/pubmed/28695888 http://dx.doi.org/10.1038/ncomms15987 |
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