Frequency of KRAS, BRAF, and NRAS mutations in colorectal cancer
Abstract
Mutational analysis of KRAS codons 12 and 13 is standard for patients with metastatic colorectal cancer since mutations in these codons predict lack of response to anti‐EGFR therapies. However, even among patients whose tumors are wildtype for KRAS codons 12 and 13, only a subset respond to therapy. Since additional activating mutations downstream of EGFR may also play a role in treatment resistance, we sought to establish the frequency of these mutations. We evaluated 2121 colorectal tumors for mutations in codons 12 and 13 of the KRAS gene. A subset of these samples, comprised of 513 samples wildtype for KRAS codons 12 and 13, were tested for mutations in codons 61 and 146 of KRAS, codon 600 of BRAF, and codons 12, 13, and 61 of NRAS. Mutation status was determined by targeted pyrosequencing. Mutations in KRAS codon 12 or 13 were identified in 900/2121 (42.4%) samples. Of the 513 wildtype samples tested for additional mutations, 78 samples were mutant for BRAF, 19 for KRAS codon 61, 17 for KRAS codon 146, and 26 for NRAS. In total, 140/513 (27.3%) tumors wildtype for KRAS codons 12 and 13 harbored a mutation in another of the RAS pathway genes. While further study is needed to determine the full therapeutic implications of mutations in these codons, mutational testing of these codons may be useful for identifying a significant proportion of patients who may also be resistant to anti‐EGFR therapies. © 2011 Wiley‐Liss, Inc.
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Aberrant RAS activation leads to persistent MAPK and PI3K/AKT signaling, driving uncontrolled cell proliferation and survival, contributing to colorectal tumorigenesis.
“This aberrant activation leads to persistent MAPK and PI3K/AKT signaling, driving uncontrolled cell proliferation and survival, thereby contributing to colorectal tumorigenesis [5].”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [5]
In colorectal epithelial cells, oncogenic KRAS or NRAS mutations most commonly affect codons 12, 13, or 61 and result in constitutive RAS activation independent of upstream EGFR stimulation.
“In colorectal epithelial cells, oncogenic mutations in KRAS or NRAS—most commonly affecting codons 12, 13, or 61—result in the constitutive activation of RAS, maintaining it in a GTP-bound state independent of upstream EGFR stimulation [5].”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [5]
Cites
Amado, R. G., Wolf, M., Peeters, M., Van Cutsem, E., Siena, S., Freeman, D. J., Juan, T., Sikorski, R., Suggs, S., Radinsky, R., et al. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2007.14.7116 · Cited by 3,207 · see citing works
<i>KRAS</i> Mutation Status Is Predictive of Response to Cetuximab Therapy in Colorectal Cancer
Lièvre, A., Bachet, J.-B., Le Corre, D., Boige, V., Landi, B., Emile, J.-F., Côté, J.-F., Tomasic, G., Penna, C., Ducreux, M., et al. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-0191 · Cited by 2,229 · see citing works
De Roock, W., Claes, B., Bernasconi, D., De Schutter, J., Biesmans, B., Fountzilas, G., Kalogeras, K. T., Kotoula, V., Papamichael, D., Laurent-Puig, P., et al. (2010) · The Lancet Oncology · doi:10.1016/s1470-2045(10)70130-3 · Cited by 2,144 · see citing works
Di Nicolantonio, F., Martini, M., Molinari, F., Sartore-Bianchi, A., Arena, S., Saletti, P., De Dosso, S., Mazzucchelli, L., Frattini, M., Siena, S., et al. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2008.18.0786 · Cited by 1,591 · cited 2× · see citing works
“…data on the response of BRAF mutated tumors (Phillips et al., 2010; Tol et al., 2010), multiple studies have suggested that mutations in other KRAS codons and other genes downstream of EGFR may also confer drug resistance (Di Nicolantonio et al., 2008; Loupakis et al., 2009; De Roock et al., 2010).”
BackgroundLièvre, A., Bachet, J., Boige, V., Cayre, A., Corre, D. L., Buc, E., Ychou, M., Bouché, O., Landi, B., Louvet, C., et al. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2007.12.5906 · Cited by 1,456 · see citing works
De Roock, W., Piessevaux, H., De Schutter, J., Janssens, M., De Hertogh, G., Personeni, N., Biesmans, B., Van Laethem, J.-L., Peeters, M., Humblet, Y., et al. (2008) · Annals of Oncology · doi:10.1093/annonc/mdm496 · Cited by 827 · see citing works
Di Fiore, F., Blanchard, F., Charbonnier, F., Le Pessot, F., Lamy, A., Galais, M. P., Bastit, L., Killian, A., Sesboüé, R., Tuech, J. J., et al. (2007) · British Journal of Cancer · doi:10.1038/sj.bjc.6603685 · Cited by 734 · see citing works
Germline KRAS mutations cause Noonan syndrome
Schubbert, S., Zenker, M., Rowe, S. L., Böll, S., Klein, C., Bollag, G., van der Burgt, I., Musante, L., Kalscheuer, V., Wehner, L.-E., et al. (2006) · Nature Genetics · doi:10.1038/ng1748 · Cited by 730 · see citing works
Laurent-Puig, P., Cayre, A., Manceau, G., Buc, E., Bachet, J.-B., Lecomte, T., Rougier, P., Lievre, A., Landi, B., Boige, V., et al. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2008.21.6796 · Cited by 673 · see citing works
Loupakis, F., Ruzzo, A., Cremolini, C., Vincenzi, B., Salvatore, L., Santini, D., Masi, G., Stasi, I., Canestrari, E., Rulli, E., et al. (2009) · British Journal of Cancer · doi:10.1038/sj.bjc.6605177 · Cited by 562 · see citing works
Richman, S. D., Seymour, M. T., Chambers, P., Elliott, F., Daly, C. L., Meade, A. M., Taylor, G., Barrett, J. H., & Quirke, P. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2009.22.4295 · Cited by 560 · see citing works
Siena, S., Bianchi, A. S., Nicolantonio, F. D., Balfour, J., & Bardelli, A. (2009) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djp280 · Cited by 526 · see citing works
Sensitive Sequencing Method for KRAS Mutation Detection by Pyrosequencing
Ogino, S., Kawasaki, T., Brahmandam, M., Yan, L., Cantor, M., Namgyal, C., Mino-Kenudson, M. A., Lauwers, G. Y., Loda, M. F., & Fuchs, C. S. (2005) · Journal of Molecular Diagnostics · doi:10.1016/s1525-1578(10)60571-5 · Cited by 488 · see citing works
Tsiatis, A. C., Norris-Kirby, A., Rich, R. G., Hafez, M. J., Gocke, C. D., Eshleman, J. R., & Murphy, K. M. (2010) · Journal of Molecular Diagnostics · doi:10.2353/jmoldx.2010.090188 · Cited by 488 · see citing works
Tol, J., Dijkstra, J. R., Klomp, M., Teerenstra, S., Dommerholt, M., Vink-Börger, M. E., van Cleef, P. H. J., van Krieken, J. H., Punt, C. J. A., & Nagtegaal, I. D. (2010) · European Journal of Cancer · doi:10.1016/j.ejca.2010.03.036 · Cited by 210 · see citing works
Simi, L., Pratesi, N., Vignoli, M., Sestini, R., Cianchi, F., Valanzano, R., Nobili, S., Mini, E., Pazzagli, M., & Orlando, C. (2008) · American Journal of Clinical Pathology · doi:10.1309/lwdy1axhxuulnvhq · Cited by 164 · see citing works
Freeman, D. J., Juan, T., Reiner, M. T., Hecht, J. R., Meropol, N. J., Berlin, J. D., Mitchell, E. P., Sarosi, I., Radinsky, R., & Amado, R. G. (2008) · Clinical Colorectal Cancer · doi:10.3816/ccc.2008.n.024 · Cited by 162 · see citing works
Alleles of APC modulate the frequency and classes of mutations that lead to colon polyps
Spirio, L. N., Samowitz, W. S., Robertson, J., et al. (1998) · Nature Genetics · doi:10.1038/3865 · Cited by 157 · see citing works
Self-citationTyner, J. W., Erickson, H., Deininger, M. W., Willis, S. G., Eide, C. A., Levine, R. L., Heinrich, M. C., Gattermann, N., Gilliland, D. G., Druker, B. J., et al. (2008) · Blood · doi:10.1182/blood-2008-04-152157 · Cited by 131 · see citing works
PIK3CA Mutations Predict Local Recurrences in Rectal Cancer Patients
He, Y., Veer, L. J. V., Mikolajewska-Hanclich, I., van Velthuysen, M. F., Zeestraten, E. C. M., Nagtegaal, I. D., van de Velde, C. J. �., & Marijnen, C. A. M. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-1165 · Cited by 100 · see citing works
Biochemical Characterization of a Novel KRAS Insertion Mutation from a Human Leukemia
Bollag, G. E., Adler, F., elMasry, N., McCabe, P. C., Conner, E. R., Thompson, P., McCormick, F. P., & Shannon, K. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.51.32491 · Cited by 63 · see citing works
RAS Signaling in Colorectal Carcinomas through Alteration of RAS, RAF, NF1, and/or RASSF1A
Ahlquist, T. C., Bottillo, I., Danielsen, S. A., Meling, G. I., Rognum, T. O., Lind, G. E., Dallapiccola, B., & Lothe, R. A. (2008) · Neoplasia · doi:10.1593/neo.08312 · Cited by 56 · see citing works
Ferraz, J., Zinzindohoué, F., Lecomte, T., et al. (2004) · International Journal of Cancer · doi:10.1002/ijc.20124 · Cited by 22 · see citing works
BRAF testing in advanced colorectal cancer: is it ready for prime time?
Phillips, B. E., Kalady, M. F., & Kim, R. (2010) · PubMed · Cited by 13 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Detection of Circulating Tumor DNA in Early- and Late-Stage Human Malignancies
Bettegowda, C., Sausen, M., Leary, R. J., Kinde, I., Wang, Y., Agrawal, N., Bartlett, B. R., Wang, H., Luber, B., Alani, R. M., et al. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3007094 · Cited by 5,067 · see citing works
ESMO consensus guidelines for the management of patients with metastatic colorectal cancer
Van Cutsem, E., Cervantes, A., Adam, R., Sobrero, A., Van Krieken, J. H., Aderka, D., Aranda Aguilar, E., Bardelli, A., Benson, A., Bodoky, G., et al. (2016) · Annals of Oncology · doi:10.1093/annonc/mdw235 · Cited by 3,421 · see citing works
Panitumumab–FOLFOX4 Treatment and <i>RAS</i> Mutations in Colorectal Cancer
Douillard, J.-Y., Oliner, K. S., Siena, S., Tabernero, J., Burkes, R., Barugel, M., Humblet, Y., Bodoky, G., Cunningham, D., Jassem, J., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1305275 · Cited by 2,263 · see citing works
T-Cell Transfer Therapy Targeting Mutant KRAS in Cancer
Tran, E., Robbins, P. F., Lu, Y.-C., Prickett, T. D., Gartner, J. J., Jia, L., Pasetto, A., Zheng, Z., Ray, S., Groh, E. M., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1609279 · Cited by 1,368 · see citing works
Immunogenicity of somatic mutations in human gastrointestinal cancers
Tran, E., Ahmadzadeh, M., Lu, Y.-C., Gros, A., Turcotte, S., Robbins, P. F., Gartner, J. J., Zheng, Z., Li, Y. F., Ray, S., et al. (2015) · Science · doi:10.1126/science.aad1253 · Cited by 729 · see citing works
Resistance to anti-EGFR therapy in colorectal cancer: From heterogeneity to convergent evolution
Misale, S., Di Nicolantonio, F., Sartore-Bianchi, A., Siena, S., & Bardelli, A. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-14-0462 · Cited by 513 · see citing works
Prognostic and Predictive Roles of KRAS Mutation in Colorectal Cancer
Arrington, A. K., Heinrich, E. L., Lee, W., Duldulao, M., Patel, S., Sanchez, J., Garcia-Aguilar, J., & Kim, J. (2012) · International Journal of Molecular Sciences · doi:10.3390/ijms131012153 · Cited by 244 · see citing works
Peeters, M., Kafatos, G., Taylor, A., Gastanaga, V. M., Oliner, K. S., Hechmati, G., Terwey, J.-H., & van Krieken, J. H. (2015) · European Journal of Cancer · doi:10.1016/j.ejca.2015.05.017 · Cited by 163 · see citing works
A pan-cancer organoid platform for precision medicine
Larsen, B. M., Kannan, M., Langer, L. F., Leibowitz, B. D., Bentaieb, A., Cancino, A., Dolgalev, I., Drummond, B. E., Dry, J. R., Ho, C.-S., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109429 · Cited by 105 · see citing works
Current targeted therapies in the treatment of advanced colorectal cancer: a review
Moriarity, A., O’Sullivan, J., Kennedy, J., Mehigan, B., & McCormick, P. (2016) · Therapeutic Advances in Medical Oncology · doi:10.1177/1758834016646734 · Cited by 87 · see citing works
Johnson, R. M., Qu, X., Lin, C.-F., Huw, L.-Y., Venkatanarayan, A., Sokol, E., Ou, F.-S., Ihuegbu, N., Zill, O. A., Kabbarah, O., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-33172-5 · Cited by 42 · see citing works
Therapeutic Targets of KRAS in Colorectal Cancer
Rahman, S., Garrel, S., Gerber, M., Maitra, R., & Goel, S. (2021) · Cancers · doi:10.3390/cancers13246233 · Cited by 28 · see citing works
Sütcüoğlu, O., Yıldırım, H. Ç., Almuradova, E., Günenç, D., & Yalçın, Ş. (2025) · Medicina · doi:10.3390/medicina61071202 · Cited by 10 · see citing works
- Authors
- Vaughn, C. P., ZoBell, S. D., Furtado, L. V., Baker, C. L., & Samowitz, W. S.
- Affiliations
- ARUP Institute for Clinical and Experimental Pathology (US)
- ARUP Laboratories (United States) (US)
- University of Utah (US)
- Corresponding author
- Samowitz, Wade S.
- Venue
- Genes, Chromosomes and Cancer
- Publisher
- Wiley
- Published
- 2011-02-08
- Volume
- 50
- Issue
- 5
- Pages
- 307-312
- ISSN
- 1045-2257 (ISSN-L)
- 1098-2264
- OpenAlex
- W2075158341
- Cited by
- 377
- References
- 24
- Citations by year
- 2026: 12 · 2025: 18 · 2024: 11 · 2023: 11 · 2022: 30 · 2021: 21 · 2020: 31 · 2019: 27 · 2018: 27 · 2017: 18 · 2016: 29 · 2015: 31 · 2014: 52 · 2013: 30 · 2012: 24
- FWCI
- 17.45
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Genes Chromosomes and Cancer (publishedVersion)
- PubMed (publishedVersion)
- Funders
- ARUP Laboratories
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- KRAS mutation, BRAF mutation, NRAS mutation, colorectal cancer, Ras signaling, anti-EGFR therapy, anti-EGFR therapy resistance, mutation frequency
- MeSH terms
- Codon, DNA Mutational Analysis, Humans, Mutation, Proto-Oncogene Proteins, Genes, ras, Colorectal Neoplasms, Proto-Oncogene Proteins p21(ras), ras Proteins, Genes, erbB-1, Proto-Oncogene Proteins B-raf
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