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Hotspot mutations delineating diverse mutational signatures and biological utilities across cancer types

BACKGROUND: An important step towards personalizing cancer treatment is to integrate heterogeneous evidences to catalog mutational hotspots that are biologically and therapeutically relevant and thus represent where targeted therapy would likely be beneficial. However, existing methods do not suffic...

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Autores principales: Chen, Tenghui, Wang, Zixing, Zhou, Wanding, Chong, Zechen, Meric-Bernstam, Funda, Mills, Gordon B., Chen, Ken
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4928158/
https://www.ncbi.nlm.nih.gov/pubmed/27356755
http://dx.doi.org/10.1186/s12864-016-2727-x
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author Chen, Tenghui
Wang, Zixing
Zhou, Wanding
Chong, Zechen
Meric-Bernstam, Funda
Mills, Gordon B.
Chen, Ken
author_facet Chen, Tenghui
Wang, Zixing
Zhou, Wanding
Chong, Zechen
Meric-Bernstam, Funda
Mills, Gordon B.
Chen, Ken
author_sort Chen, Tenghui
collection PubMed
description BACKGROUND: An important step towards personalizing cancer treatment is to integrate heterogeneous evidences to catalog mutational hotspots that are biologically and therapeutically relevant and thus represent where targeted therapy would likely be beneficial. However, existing methods do not sufficiently delineate varying functionality of individual mutations within the same genes. RESULTS: We observed a large discordancy of mutation rates across different mutation subtypes and tumor types, and nominated 702 hotspot mutations in 549 genes in the Catalog of Somatic Mutations in Cancer (COSMIC) by considering context specific mutation characteristics such as genes, cancer types, mutation rates, mutation subtypes and sequence contexts. We observed that hotspot mutations were highly prevalent in Non CpG-island C/G transition and transversion sequence contexts in 10 tumor types, and specific insertion hotspot mutations were enriched in breast cancer and deletion hotspot mutations in colorectal cancer. We found that the hotspot mutations nominated by our approach were significantly more conserved than non-hotspot mutations in the corresponding cancer genes. We also examined the biological significance and pharmacogenomics properties of these hotspot mutations using data in the Cancer Genome Atlas (TCGA) and the Cancer Cell-Line Encyclopedia (CCLE), and found that 53 hotspot mutations are independently associated with diverse functional evidences in 1) mRNA and protein expression, 2) pathway activity, or 3) drug sensitivity and 82 were highly enriched in specific tumor types. We highlighted the distinct functional indications of hotspot mutations under different contexts and nominated novel hotspot mutations such as MAP3K4 A1199 deletion, NR1H2 Q175 insertion, and GATA3 P409 insertion as potential biomarkers or drug targets. CONCLUSION: We identified a set of hotspot mutations across 17 tumor types by considering the background mutation rate variations among genes, tumor subtypes, mutation subtypes, and sequence contexts. We illustrated the common and distinct mutational signatures of hotspot mutations among different tumor types and investigated their variable functional relevance under different contexts, which could potentially serve as a resource for explicitly selecting targets for diagnosis, drug development, and patient management. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12864-016-2727-x) contains supplementary material, which is available to authorized users.
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spelling pubmed-49281582016-06-30 Hotspot mutations delineating diverse mutational signatures and biological utilities across cancer types Chen, Tenghui Wang, Zixing Zhou, Wanding Chong, Zechen Meric-Bernstam, Funda Mills, Gordon B. Chen, Ken BMC Genomics Research Article BACKGROUND: An important step towards personalizing cancer treatment is to integrate heterogeneous evidences to catalog mutational hotspots that are biologically and therapeutically relevant and thus represent where targeted therapy would likely be beneficial. However, existing methods do not sufficiently delineate varying functionality of individual mutations within the same genes. RESULTS: We observed a large discordancy of mutation rates across different mutation subtypes and tumor types, and nominated 702 hotspot mutations in 549 genes in the Catalog of Somatic Mutations in Cancer (COSMIC) by considering context specific mutation characteristics such as genes, cancer types, mutation rates, mutation subtypes and sequence contexts. We observed that hotspot mutations were highly prevalent in Non CpG-island C/G transition and transversion sequence contexts in 10 tumor types, and specific insertion hotspot mutations were enriched in breast cancer and deletion hotspot mutations in colorectal cancer. We found that the hotspot mutations nominated by our approach were significantly more conserved than non-hotspot mutations in the corresponding cancer genes. We also examined the biological significance and pharmacogenomics properties of these hotspot mutations using data in the Cancer Genome Atlas (TCGA) and the Cancer Cell-Line Encyclopedia (CCLE), and found that 53 hotspot mutations are independently associated with diverse functional evidences in 1) mRNA and protein expression, 2) pathway activity, or 3) drug sensitivity and 82 were highly enriched in specific tumor types. We highlighted the distinct functional indications of hotspot mutations under different contexts and nominated novel hotspot mutations such as MAP3K4 A1199 deletion, NR1H2 Q175 insertion, and GATA3 P409 insertion as potential biomarkers or drug targets. CONCLUSION: We identified a set of hotspot mutations across 17 tumor types by considering the background mutation rate variations among genes, tumor subtypes, mutation subtypes, and sequence contexts. We illustrated the common and distinct mutational signatures of hotspot mutations among different tumor types and investigated their variable functional relevance under different contexts, which could potentially serve as a resource for explicitly selecting targets for diagnosis, drug development, and patient management. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12864-016-2727-x) contains supplementary material, which is available to authorized users. BioMed Central 2016-06-23 /pmc/articles/PMC4928158/ /pubmed/27356755 http://dx.doi.org/10.1186/s12864-016-2727-x Text en © Chen et al. 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Chen, Tenghui
Wang, Zixing
Zhou, Wanding
Chong, Zechen
Meric-Bernstam, Funda
Mills, Gordon B.
Chen, Ken
Hotspot mutations delineating diverse mutational signatures and biological utilities across cancer types
title Hotspot mutations delineating diverse mutational signatures and biological utilities across cancer types
title_full Hotspot mutations delineating diverse mutational signatures and biological utilities across cancer types
title_fullStr Hotspot mutations delineating diverse mutational signatures and biological utilities across cancer types
title_full_unstemmed Hotspot mutations delineating diverse mutational signatures and biological utilities across cancer types
title_short Hotspot mutations delineating diverse mutational signatures and biological utilities across cancer types
title_sort hotspot mutations delineating diverse mutational signatures and biological utilities across cancer types
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4928158/
https://www.ncbi.nlm.nih.gov/pubmed/27356755
http://dx.doi.org/10.1186/s12864-016-2727-x
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