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Activating K-Ras mutations outwith ‘hotspot’ codons in sporadic colorectal tumours – implications for personalised cancer medicine
BACKGROUND: Response to EGFR-targeted therapies in colorectal cancer patients has been convincingly associated with Kirsten-Ras (K-Ras) mutation status. Current mandatory mutation testing for patient selection is limited to the K-Ras ‘hotspot’ codons 12 and 13. METHODS: Colorectal tumours (n=106) we...
Autores principales: | , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Nature Publishing Group
2010
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2837563/ https://www.ncbi.nlm.nih.gov/pubmed/20147967 http://dx.doi.org/10.1038/sj.bjc.6605534 |
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author | Smith, G Bounds, R Wolf, H Steele, R J C Carey, F A Wolf, C R |
author_facet | Smith, G Bounds, R Wolf, H Steele, R J C Carey, F A Wolf, C R |
author_sort | Smith, G |
collection | PubMed |
description | BACKGROUND: Response to EGFR-targeted therapies in colorectal cancer patients has been convincingly associated with Kirsten-Ras (K-Ras) mutation status. Current mandatory mutation testing for patient selection is limited to the K-Ras ‘hotspot’ codons 12 and 13. METHODS: Colorectal tumours (n=106) were screened for additional K-Ras mutations, phenotypes compared in transformation and Ras GTPase activating assays and gene and pathway changes induced by individual K-Ras mutants identified by microarray analysis. Taqman-based gene copy number and FISH analyses were used to investigate K-Ras gene amplification. RESULTS: Four additional K-Ras mutations (Leu(19)Phe (1 out of 106 tumours), Lys(117)Asn (1 out of 106), Ala(146)Thr (7 out of 106) and Arg(164)Gln (1 out of 106)) were identified. Lys(117)Asn and Ala(146)Thr had phenotypes similar to the hotspot mutations, whereas Leu(19)Phe had an attenuated phenotype and the Arg(164)Gln mutation was phenotypically equivalent to wt K-Ras. We additionally identified a new K-Ras gene amplification event, present in approximately 2% of tumours. CONCLUSIONS: The identification of mutations outwith previously described hotspot codons increases the K-Ras mutation burden in colorectal tumours by one-third. Future mutation screening to facilitate optimal patient selection for treatment with EGFR-targeted therapies should therefore be extended to codon 146, and in addition should consider the unique molecular signatures associated with individual K-Ras mutations. |
format | Text |
id | pubmed-2837563 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-28375632011-02-16 Activating K-Ras mutations outwith ‘hotspot’ codons in sporadic colorectal tumours – implications for personalised cancer medicine Smith, G Bounds, R Wolf, H Steele, R J C Carey, F A Wolf, C R Br J Cancer Translational Therapeutics BACKGROUND: Response to EGFR-targeted therapies in colorectal cancer patients has been convincingly associated with Kirsten-Ras (K-Ras) mutation status. Current mandatory mutation testing for patient selection is limited to the K-Ras ‘hotspot’ codons 12 and 13. METHODS: Colorectal tumours (n=106) were screened for additional K-Ras mutations, phenotypes compared in transformation and Ras GTPase activating assays and gene and pathway changes induced by individual K-Ras mutants identified by microarray analysis. Taqman-based gene copy number and FISH analyses were used to investigate K-Ras gene amplification. RESULTS: Four additional K-Ras mutations (Leu(19)Phe (1 out of 106 tumours), Lys(117)Asn (1 out of 106), Ala(146)Thr (7 out of 106) and Arg(164)Gln (1 out of 106)) were identified. Lys(117)Asn and Ala(146)Thr had phenotypes similar to the hotspot mutations, whereas Leu(19)Phe had an attenuated phenotype and the Arg(164)Gln mutation was phenotypically equivalent to wt K-Ras. We additionally identified a new K-Ras gene amplification event, present in approximately 2% of tumours. CONCLUSIONS: The identification of mutations outwith previously described hotspot codons increases the K-Ras mutation burden in colorectal tumours by one-third. Future mutation screening to facilitate optimal patient selection for treatment with EGFR-targeted therapies should therefore be extended to codon 146, and in addition should consider the unique molecular signatures associated with individual K-Ras mutations. Nature Publishing Group 2010-02-16 2010-02-16 /pmc/articles/PMC2837563/ /pubmed/20147967 http://dx.doi.org/10.1038/sj.bjc.6605534 Text en Copyright © 2010 Cancer Research UK https://creativecommons.org/licenses/by/4.0/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 https://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Translational Therapeutics Smith, G Bounds, R Wolf, H Steele, R J C Carey, F A Wolf, C R Activating K-Ras mutations outwith ‘hotspot’ codons in sporadic colorectal tumours – implications for personalised cancer medicine |
title | Activating K-Ras mutations outwith ‘hotspot’ codons in sporadic colorectal tumours – implications for personalised cancer medicine |
title_full | Activating K-Ras mutations outwith ‘hotspot’ codons in sporadic colorectal tumours – implications for personalised cancer medicine |
title_fullStr | Activating K-Ras mutations outwith ‘hotspot’ codons in sporadic colorectal tumours – implications for personalised cancer medicine |
title_full_unstemmed | Activating K-Ras mutations outwith ‘hotspot’ codons in sporadic colorectal tumours – implications for personalised cancer medicine |
title_short | Activating K-Ras mutations outwith ‘hotspot’ codons in sporadic colorectal tumours – implications for personalised cancer medicine |
title_sort | activating k-ras mutations outwith ‘hotspot’ codons in sporadic colorectal tumours – implications for personalised cancer medicine |
topic | Translational Therapeutics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2837563/ https://www.ncbi.nlm.nih.gov/pubmed/20147967 http://dx.doi.org/10.1038/sj.bjc.6605534 |
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