<i>KRAS, NRAS, BRAF, HER2</i> 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). <i>KRAS</i>, <i>NRAS</i> and <i>BRAF</i> mutations, <i>HER2</i> ampl...
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MDPI AG
2023-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/5/4868 |
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| author | Aleksandr S. Martianov Natalia V. Mitiushkina Anastasia N. Ershova Darya E. Martynenko Mikhail G. Bubnov Priscilla Amankwah Grigory A. Yanus Svetlana N. Aleksakhina Vladislav I. Tiurin Aigul R. Venina Aleksandra A. Anuskina Yuliy A. Gorgul Anna D. Shestakova Mikhail A. Maidin Alexey M. Belyaev Liliya S. Baboshkina Aglaya G. Iyevleva Evgeny N. Imyanitov |
| author_facet | Aleksandr S. Martianov Natalia V. Mitiushkina Anastasia N. Ershova Darya E. Martynenko Mikhail G. Bubnov Priscilla Amankwah Grigory A. Yanus Svetlana N. Aleksakhina Vladislav I. Tiurin Aigul R. Venina Aleksandra A. Anuskina Yuliy A. Gorgul Anna D. Shestakova Mikhail A. Maidin Alexey M. Belyaev Liliya S. Baboshkina Aglaya G. Iyevleva Evgeny N. Imyanitov |
| author_sort | Aleksandr S. Martianov |
| collection | DOAJ |
| 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). <i>KRAS</i>, <i>NRAS</i> and <i>BRAF</i> mutations, <i>HER2</i> amplification and overexpression, and microsatellite instability (MSI) were tested in 8355 CRC samples. <i>KRAS</i> 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. <i>KRAS</i> Q61K substitution, which leads to the aberrant splicing of the gene, was accompanied by the second function-rescuing mutation in all 19 tumors analyzed. <i>NRAS</i> mutations were detected in 389/8355 (4.7%) CRCs (379 hot-spot and 10 non-hot-spot substitutions). <i>BRAF</i> 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, <i>BRAF</i> 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, <i>p</i> = 0.0007). The simultaneous presence of two drug targets, <i>BRAF</i> 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 (<i>KRAS</i>/<i>NRAS</i>: 8; <i>KRAS</i>/<i>BRAF</i>: 4; <i>KRAS</i>/<i>HER2</i>: 12; <i>NRAS</i>/<i>HER2</i>: 4). This study demonstrates that a substantial portion of <i>RAS</i> alterations is represented by atypical mutations, <i>KRAS</i> Q61K substitution is always accompanied by the second gene-rescuing mutation, <i>BRAF</i> mutation frequency is a subject to geographical variations, and a small fraction of CRCs has simultaneous alterations in more than one driver gene. |
| first_indexed | 2024-03-11T07:21:45Z |
| format | Article |
| id | doaj.art-a169542c441740c8ad3333e7f0a1b1f3 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T07:21:45Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-a169542c441740c8ad3333e7f0a1b1f32023-11-17T07:54:30ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-03-01245486810.3390/ijms24054868<i>KRAS, NRAS, BRAF, HER2</i> and MSI Status in a Large Consecutive Series of Colorectal CarcinomasAleksandr S. Martianov0Natalia V. Mitiushkina1Anastasia N. Ershova2Darya E. Martynenko3Mikhail G. Bubnov4Priscilla Amankwah5Grigory A. Yanus6Svetlana N. Aleksakhina7Vladislav I. Tiurin8Aigul R. Venina9Aleksandra A. Anuskina10Yuliy A. Gorgul11Anna D. Shestakova12Mikhail A. Maidin13Alexey M. Belyaev14Liliya S. Baboshkina15Aglaya G. Iyevleva16Evgeny N. Imyanitov17Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 St. Petersburg, RussiaDepartment of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 St. Petersburg, RussiaDepartment of Medical Genetics, St.-Petersburg Pediatric Medical University, 194100 St. Petersburg, RussiaDepartment of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 St. Petersburg, RussiaDepartment of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 St. Petersburg, RussiaDepartment of Medical Genetics, St.-Petersburg Pediatric Medical University, 194100 St. Petersburg, RussiaDepartment of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 St. Petersburg, RussiaDepartment of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 St. Petersburg, RussiaDepartment of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 St. Petersburg, RussiaDepartment of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 St. Petersburg, RussiaDepartment of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 St. Petersburg, RussiaDepartment of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 St. Petersburg, RussiaDepartment of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 St. Petersburg, RussiaDepartment of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 St. Petersburg, RussiaDepartment of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 St. Petersburg, RussiaDepartment of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 St. Petersburg, RussiaDepartment of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 St. Petersburg, RussiaDepartment of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 St. Petersburg, RussiaThis study aimed to analyze clinical and regional factors influencing the distribution of actionable genetic alterations in a large consecutive series of colorectal carcinomas (CRCs). <i>KRAS</i>, <i>NRAS</i> and <i>BRAF</i> mutations, <i>HER2</i> amplification and overexpression, and microsatellite instability (MSI) were tested in 8355 CRC samples. <i>KRAS</i> 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. <i>KRAS</i> Q61K substitution, which leads to the aberrant splicing of the gene, was accompanied by the second function-rescuing mutation in all 19 tumors analyzed. <i>NRAS</i> mutations were detected in 389/8355 (4.7%) CRCs (379 hot-spot and 10 non-hot-spot substitutions). <i>BRAF</i> 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, <i>BRAF</i> 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, <i>p</i> = 0.0007). The simultaneous presence of two drug targets, <i>BRAF</i> 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 (<i>KRAS</i>/<i>NRAS</i>: 8; <i>KRAS</i>/<i>BRAF</i>: 4; <i>KRAS</i>/<i>HER2</i>: 12; <i>NRAS</i>/<i>HER2</i>: 4). This study demonstrates that a substantial portion of <i>RAS</i> alterations is represented by atypical mutations, <i>KRAS</i> Q61K substitution is always accompanied by the second gene-rescuing mutation, <i>BRAF</i> mutation frequency is a subject to geographical variations, and a small fraction of CRCs has simultaneous alterations in more than one driver gene.https://www.mdpi.com/1422-0067/24/5/4868<i>KRAS</i><i>NRAS</i><i>BRAF</i>microsatellite instability<i>HER2</i>colorectal cancer |
| spellingShingle | Aleksandr S. Martianov Natalia V. Mitiushkina Anastasia N. Ershova Darya E. Martynenko Mikhail G. Bubnov Priscilla Amankwah Grigory A. Yanus Svetlana N. Aleksakhina Vladislav I. Tiurin Aigul R. Venina Aleksandra A. Anuskina Yuliy A. Gorgul Anna D. Shestakova Mikhail A. Maidin Alexey M. Belyaev Liliya S. Baboshkina Aglaya G. Iyevleva Evgeny N. Imyanitov <i>KRAS, NRAS, BRAF, HER2</i> and MSI Status in a Large Consecutive Series of Colorectal Carcinomas International Journal of Molecular Sciences <i>KRAS</i> <i>NRAS</i> <i>BRAF</i> microsatellite instability <i>HER2</i> colorectal cancer |
| title | <i>KRAS, NRAS, BRAF, HER2</i> and MSI Status in a Large Consecutive Series of Colorectal Carcinomas |
| title_full | <i>KRAS, NRAS, BRAF, HER2</i> and MSI Status in a Large Consecutive Series of Colorectal Carcinomas |
| title_fullStr | <i>KRAS, NRAS, BRAF, HER2</i> and MSI Status in a Large Consecutive Series of Colorectal Carcinomas |
| title_full_unstemmed | <i>KRAS, NRAS, BRAF, HER2</i> and MSI Status in a Large Consecutive Series of Colorectal Carcinomas |
| title_short | <i>KRAS, NRAS, BRAF, HER2</i> and MSI Status in a Large Consecutive Series of Colorectal Carcinomas |
| title_sort | i kras nras braf her2 i and msi status in a large consecutive series of colorectal carcinomas |
| topic | <i>KRAS</i> <i>NRAS</i> <i>BRAF</i> microsatellite instability <i>HER2</i> colorectal cancer |
| url | https://www.mdpi.com/1422-0067/24/5/4868 |
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