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Pancancer modelling predicts the context-specific impact of somatic mutations on transcriptional programs
Pancancer studies have identified many genes that are frequently somatically altered across multiple tumour types, suggesting that pathway-targeted therapies can be deployed across diverse cancers. However, the same ‘actionable mutation' impacts distinct context-specific gene regulatory program...
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/PMC5290314/ https://www.ncbi.nlm.nih.gov/pubmed/28139702 http://dx.doi.org/10.1038/ncomms14249 |
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author | Osmanbeyoglu, Hatice U. Toska, Eneda Chan, Carmen Baselga, José Leslie, Christina S. |
author_facet | Osmanbeyoglu, Hatice U. Toska, Eneda Chan, Carmen Baselga, José Leslie, Christina S. |
author_sort | Osmanbeyoglu, Hatice U. |
collection | PubMed |
description | Pancancer studies have identified many genes that are frequently somatically altered across multiple tumour types, suggesting that pathway-targeted therapies can be deployed across diverse cancers. However, the same ‘actionable mutation' impacts distinct context-specific gene regulatory programs and signalling networks—and interacts with different genetic backgrounds of co-occurring alterations—in different cancers. Here we apply a computational strategy for integrating parallel (phospho)proteomic and mRNA sequencing data across 12 TCGA tumour data sets to interpret the context-specific impact of somatic alterations in terms of functional signatures such as (phospho)protein and transcription factor (TF) activities. Our analysis predicts distinct dysregulated transcriptional regulators downstream of somatic alterations in different cancers, and we validate the context-specific differential activity of TFs associated to mutant PIK3CA in isogenic cancer cell line models. These results have implications for the pancancer use of targeted drugs and potentially for the design of combination therapies. |
format | Online Article Text |
id | pubmed-5290314 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-52903142017-02-07 Pancancer modelling predicts the context-specific impact of somatic mutations on transcriptional programs Osmanbeyoglu, Hatice U. Toska, Eneda Chan, Carmen Baselga, José Leslie, Christina S. Nat Commun Article Pancancer studies have identified many genes that are frequently somatically altered across multiple tumour types, suggesting that pathway-targeted therapies can be deployed across diverse cancers. However, the same ‘actionable mutation' impacts distinct context-specific gene regulatory programs and signalling networks—and interacts with different genetic backgrounds of co-occurring alterations—in different cancers. Here we apply a computational strategy for integrating parallel (phospho)proteomic and mRNA sequencing data across 12 TCGA tumour data sets to interpret the context-specific impact of somatic alterations in terms of functional signatures such as (phospho)protein and transcription factor (TF) activities. Our analysis predicts distinct dysregulated transcriptional regulators downstream of somatic alterations in different cancers, and we validate the context-specific differential activity of TFs associated to mutant PIK3CA in isogenic cancer cell line models. These results have implications for the pancancer use of targeted drugs and potentially for the design of combination therapies. Nature Publishing Group 2017-01-31 /pmc/articles/PMC5290314/ /pubmed/28139702 http://dx.doi.org/10.1038/ncomms14249 Text en Copyright © 2017, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Osmanbeyoglu, Hatice U. Toska, Eneda Chan, Carmen Baselga, José Leslie, Christina S. Pancancer modelling predicts the context-specific impact of somatic mutations on transcriptional programs |
title | Pancancer modelling predicts the context-specific impact of somatic mutations on transcriptional programs |
title_full | Pancancer modelling predicts the context-specific impact of somatic mutations on transcriptional programs |
title_fullStr | Pancancer modelling predicts the context-specific impact of somatic mutations on transcriptional programs |
title_full_unstemmed | Pancancer modelling predicts the context-specific impact of somatic mutations on transcriptional programs |
title_short | Pancancer modelling predicts the context-specific impact of somatic mutations on transcriptional programs |
title_sort | pancancer modelling predicts the context-specific impact of somatic mutations on transcriptional programs |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5290314/ https://www.ncbi.nlm.nih.gov/pubmed/28139702 http://dx.doi.org/10.1038/ncomms14249 |
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