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

Authors :
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
Source :
International Journal of Molecular Sciences, Volume 24, Issue 5, Pages: 4868
Publication Year :
2023
Publisher :
MDPI AG, 2023.

Abstract

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.

Details

ISSN :
14220067
Volume :
24
Database :
OpenAIRE
Journal :
International Journal of Molecular Sciences
Accession number :
edsair.doi.dedup.....bdecc5a970257f7d069339ddef51dfc2
Full Text :
https://doi.org/10.3390/ijms24054868