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Uncommon mutational profiles of metastatic colorectal cancer detected during routine genotyping using next generation sequencing

RAS genotyping is mandatory to predict anti-EGFR monoclonal antibodies (mAbs) therapy resistance and BRAF genotyping is a relevant prognosis marker in patients with metastatic colorectal cancer. Although the role of hotspot mutations is well defined, the impact of uncommon mutations is still unknown...

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Autores principales: Franczak, Claire, Kandathil, Shaun M., Gilson, Pauline, Husson, Marie, Rouyer, Marie, Demange, Jessica, Leroux, Agnès, Merlin, Jean-Louis, Harlé, Alexandre
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506598/
https://www.ncbi.nlm.nih.gov/pubmed/31068650
http://dx.doi.org/10.1038/s41598-019-43646-0
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author Franczak, Claire
Kandathil, Shaun M.
Gilson, Pauline
Husson, Marie
Rouyer, Marie
Demange, Jessica
Leroux, Agnès
Merlin, Jean-Louis
Harlé, Alexandre
author_facet Franczak, Claire
Kandathil, Shaun M.
Gilson, Pauline
Husson, Marie
Rouyer, Marie
Demange, Jessica
Leroux, Agnès
Merlin, Jean-Louis
Harlé, Alexandre
author_sort Franczak, Claire
collection PubMed
description RAS genotyping is mandatory to predict anti-EGFR monoclonal antibodies (mAbs) therapy resistance and BRAF genotyping is a relevant prognosis marker in patients with metastatic colorectal cancer. Although the role of hotspot mutations is well defined, the impact of uncommon mutations is still unknown. In this study, we aimed to discuss the potential utility of detecting uncommon RAS and BRAF mutation profiles with next-generation sequencing. A total of 779 FFPE samples from patients with metastatic colorectal cancer with valid NGS results were screened and 22 uncommon mutational profiles of KRAS, NRAS and BRAF genes were selected. In silico prediction of mutation impact was then assessed by 2 predictive scores and a structural protein modelling. Three samples carry a single KRAS non-hotspot mutation, one a single NRAS non-hotspot mutation, four a single BRAF non-hotspot mutation and fourteen carry several mutations. This in silico study shows that some non-hotspot RAS mutations seem to behave like hotspot mutations and warrant further examination to assess whether they should confer a resistance to anti-EGFR mAbs therapy for patients bearing these non-hotspot RAS mutations. For BRAF gene, non-V600E mutations may characterise a novel subtype of mCRC with better prognosis, potentially implying a modification of therapeutic strategy.
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spelling pubmed-65065982019-05-21 Uncommon mutational profiles of metastatic colorectal cancer detected during routine genotyping using next generation sequencing Franczak, Claire Kandathil, Shaun M. Gilson, Pauline Husson, Marie Rouyer, Marie Demange, Jessica Leroux, Agnès Merlin, Jean-Louis Harlé, Alexandre Sci Rep Article RAS genotyping is mandatory to predict anti-EGFR monoclonal antibodies (mAbs) therapy resistance and BRAF genotyping is a relevant prognosis marker in patients with metastatic colorectal cancer. Although the role of hotspot mutations is well defined, the impact of uncommon mutations is still unknown. In this study, we aimed to discuss the potential utility of detecting uncommon RAS and BRAF mutation profiles with next-generation sequencing. A total of 779 FFPE samples from patients with metastatic colorectal cancer with valid NGS results were screened and 22 uncommon mutational profiles of KRAS, NRAS and BRAF genes were selected. In silico prediction of mutation impact was then assessed by 2 predictive scores and a structural protein modelling. Three samples carry a single KRAS non-hotspot mutation, one a single NRAS non-hotspot mutation, four a single BRAF non-hotspot mutation and fourteen carry several mutations. This in silico study shows that some non-hotspot RAS mutations seem to behave like hotspot mutations and warrant further examination to assess whether they should confer a resistance to anti-EGFR mAbs therapy for patients bearing these non-hotspot RAS mutations. For BRAF gene, non-V600E mutations may characterise a novel subtype of mCRC with better prognosis, potentially implying a modification of therapeutic strategy. Nature Publishing Group UK 2019-05-08 /pmc/articles/PMC6506598/ /pubmed/31068650 http://dx.doi.org/10.1038/s41598-019-43646-0 Text en © The Author(s) 2019 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
Franczak, Claire
Kandathil, Shaun M.
Gilson, Pauline
Husson, Marie
Rouyer, Marie
Demange, Jessica
Leroux, Agnès
Merlin, Jean-Louis
Harlé, Alexandre
Uncommon mutational profiles of metastatic colorectal cancer detected during routine genotyping using next generation sequencing
title Uncommon mutational profiles of metastatic colorectal cancer detected during routine genotyping using next generation sequencing
title_full Uncommon mutational profiles of metastatic colorectal cancer detected during routine genotyping using next generation sequencing
title_fullStr Uncommon mutational profiles of metastatic colorectal cancer detected during routine genotyping using next generation sequencing
title_full_unstemmed Uncommon mutational profiles of metastatic colorectal cancer detected during routine genotyping using next generation sequencing
title_short Uncommon mutational profiles of metastatic colorectal cancer detected during routine genotyping using next generation sequencing
title_sort uncommon mutational profiles of metastatic colorectal cancer detected during routine genotyping using next generation sequencing
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506598/
https://www.ncbi.nlm.nih.gov/pubmed/31068650
http://dx.doi.org/10.1038/s41598-019-43646-0
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