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KRAS, NRAS, BRAF, HER2 and MSI Status in a Large Consecutive Series of Colorectal Carcinomas

This study aimed to analyze clinical and regional factors influencing the distribution of actionable genetic alterations in a large consecutive series of colorectal carcinomas (CRCs). KRAS, NRAS and BRAF mutations, HER2 amplification and overexpression, and microsatellite instability (MSI) were test...

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Autores principales: Martianov, Aleksandr S., Mitiushkina, Natalia V., Ershova, Anastasia N., Martynenko, Darya E., Bubnov, Mikhail G., Amankwah, Priscilla, Yanus, Grigory A., Aleksakhina, Svetlana N., Tiurin, Vladislav I., Venina, Aigul R., Anuskina, Aleksandra A., Gorgul, Yuliy A., Shestakova, Anna D., Maidin, Mikhail A., Belyaev, Alexey M., Baboshkina, Liliya S., Iyevleva, Aglaya G., Imyanitov, Evgeny N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10003572/
https://www.ncbi.nlm.nih.gov/pubmed/36902296
http://dx.doi.org/10.3390/ijms24054868
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author Martianov, Aleksandr S.
Mitiushkina, Natalia V.
Ershova, Anastasia N.
Martynenko, Darya E.
Bubnov, Mikhail G.
Amankwah, Priscilla
Yanus, Grigory A.
Aleksakhina, Svetlana N.
Tiurin, Vladislav I.
Venina, Aigul R.
Anuskina, Aleksandra A.
Gorgul, Yuliy A.
Shestakova, Anna D.
Maidin, Mikhail A.
Belyaev, Alexey M.
Baboshkina, Liliya S.
Iyevleva, Aglaya G.
Imyanitov, Evgeny N.
author_facet Martianov, Aleksandr S.
Mitiushkina, Natalia V.
Ershova, Anastasia N.
Martynenko, Darya E.
Bubnov, Mikhail G.
Amankwah, Priscilla
Yanus, Grigory A.
Aleksakhina, Svetlana N.
Tiurin, Vladislav I.
Venina, Aigul R.
Anuskina, Aleksandra A.
Gorgul, Yuliy A.
Shestakova, Anna D.
Maidin, Mikhail A.
Belyaev, Alexey M.
Baboshkina, Liliya S.
Iyevleva, Aglaya G.
Imyanitov, Evgeny N.
author_sort Martianov, Aleksandr S.
collection PubMed
description This study aimed to analyze clinical and regional factors influencing the distribution of actionable genetic alterations in a large consecutive series of colorectal carcinomas (CRCs). KRAS, NRAS and BRAF mutations, HER2 amplification and overexpression, and microsatellite instability (MSI) were tested in 8355 CRC samples. KRAS mutations were detected in 4137/8355 (49.5%) CRCs, with 3913 belonging to 10 common substitutions affecting codons 12/13/61/146, 174 being represented by 21 rare hot-spot variants, and 35 located outside the “hot” codons. KRAS Q61K substitution, which leads to the aberrant splicing of the gene, was accompanied by the second function-rescuing mutation in all 19 tumors analyzed. NRAS mutations were detected in 389/8355 (4.7%) CRCs (379 hot-spot and 10 non-hot-spot substitutions). BRAF mutations were identified in 556/8355 (6.7%) CRCs (codon 600: 510; codons 594–596: 38; codons 597–602: 8). The frequency of HER2 activation and MSI was 99/8008 (1.2%) and 432/8355 (5.2%), respectively. Some of the above events demonstrated differences in distribution according to patients’ age and gender. In contrast to other genetic alterations, BRAF mutation frequencies were subject to geographic variation, with a relatively low incidence in areas with an apparently warmer climate (83/1726 (4.8%) in Southern Russia and North Caucasus vs. 473/6629 (7.1%) in other regions of Russia, p = 0.0007). The simultaneous presence of two drug targets, BRAF mutation and MSI, was observed in 117/8355 cases (1.4%). Combined alterations of two driver genes were detected in 28/8355 (0.3%) tumors (KRAS/NRAS: 8; KRAS/BRAF: 4; KRAS/HER2: 12; NRAS/HER2: 4). This study demonstrates that a substantial portion of RAS alterations is represented by atypical mutations, KRAS Q61K substitution is always accompanied by the second gene-rescuing mutation, BRAF mutation frequency is a subject to geographical variations, and a small fraction of CRCs has simultaneous alterations in more than one driver gene.
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spelling pubmed-100035722023-03-11 KRAS, NRAS, BRAF, HER2 and MSI Status in a Large Consecutive Series of Colorectal Carcinomas Martianov, Aleksandr S. Mitiushkina, Natalia V. Ershova, Anastasia N. Martynenko, Darya E. Bubnov, Mikhail G. Amankwah, Priscilla Yanus, Grigory A. Aleksakhina, Svetlana N. Tiurin, Vladislav I. Venina, Aigul R. Anuskina, Aleksandra A. Gorgul, Yuliy A. Shestakova, Anna D. Maidin, Mikhail A. Belyaev, Alexey M. Baboshkina, Liliya S. Iyevleva, Aglaya G. Imyanitov, Evgeny N. Int J Mol Sci Article This study aimed to analyze clinical and regional factors influencing the distribution of actionable genetic alterations in a large consecutive series of colorectal carcinomas (CRCs). KRAS, NRAS and BRAF mutations, HER2 amplification and overexpression, and microsatellite instability (MSI) were tested in 8355 CRC samples. KRAS mutations were detected in 4137/8355 (49.5%) CRCs, with 3913 belonging to 10 common substitutions affecting codons 12/13/61/146, 174 being represented by 21 rare hot-spot variants, and 35 located outside the “hot” codons. KRAS Q61K substitution, which leads to the aberrant splicing of the gene, was accompanied by the second function-rescuing mutation in all 19 tumors analyzed. NRAS mutations were detected in 389/8355 (4.7%) CRCs (379 hot-spot and 10 non-hot-spot substitutions). BRAF mutations were identified in 556/8355 (6.7%) CRCs (codon 600: 510; codons 594–596: 38; codons 597–602: 8). The frequency of HER2 activation and MSI was 99/8008 (1.2%) and 432/8355 (5.2%), respectively. Some of the above events demonstrated differences in distribution according to patients’ age and gender. In contrast to other genetic alterations, BRAF mutation frequencies were subject to geographic variation, with a relatively low incidence in areas with an apparently warmer climate (83/1726 (4.8%) in Southern Russia and North Caucasus vs. 473/6629 (7.1%) in other regions of Russia, p = 0.0007). The simultaneous presence of two drug targets, BRAF mutation and MSI, was observed in 117/8355 cases (1.4%). Combined alterations of two driver genes were detected in 28/8355 (0.3%) tumors (KRAS/NRAS: 8; KRAS/BRAF: 4; KRAS/HER2: 12; NRAS/HER2: 4). This study demonstrates that a substantial portion of RAS alterations is represented by atypical mutations, KRAS Q61K substitution is always accompanied by the second gene-rescuing mutation, BRAF mutation frequency is a subject to geographical variations, and a small fraction of CRCs has simultaneous alterations in more than one driver gene. MDPI 2023-03-02 /pmc/articles/PMC10003572/ /pubmed/36902296 http://dx.doi.org/10.3390/ijms24054868 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Martianov, Aleksandr S.
Mitiushkina, Natalia V.
Ershova, Anastasia N.
Martynenko, Darya E.
Bubnov, Mikhail G.
Amankwah, Priscilla
Yanus, Grigory A.
Aleksakhina, Svetlana N.
Tiurin, Vladislav I.
Venina, Aigul R.
Anuskina, Aleksandra A.
Gorgul, Yuliy A.
Shestakova, Anna D.
Maidin, Mikhail A.
Belyaev, Alexey M.
Baboshkina, Liliya S.
Iyevleva, Aglaya G.
Imyanitov, Evgeny N.
KRAS, NRAS, BRAF, HER2 and MSI Status in a Large Consecutive Series of Colorectal Carcinomas
title KRAS, NRAS, BRAF, HER2 and MSI Status in a Large Consecutive Series of Colorectal Carcinomas
title_full KRAS, NRAS, BRAF, HER2 and MSI Status in a Large Consecutive Series of Colorectal Carcinomas
title_fullStr KRAS, NRAS, BRAF, HER2 and MSI Status in a Large Consecutive Series of Colorectal Carcinomas
title_full_unstemmed KRAS, NRAS, BRAF, HER2 and MSI Status in a Large Consecutive Series of Colorectal Carcinomas
title_short KRAS, NRAS, BRAF, HER2 and MSI Status in a Large Consecutive Series of Colorectal Carcinomas
title_sort kras, nras, braf, her2 and msi status in a large consecutive series of colorectal carcinomas
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10003572/
https://www.ncbi.nlm.nih.gov/pubmed/36902296
http://dx.doi.org/10.3390/ijms24054868
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