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A Comprehensive Survey of Ras Mutations in Cancer
Open accessAbstract
All mammalian cells express 3 closely related Ras proteins, termed H-Ras, K-Ras, and N-Ras, that promote oncogenesis when they are mutationally activated at codon 12, 13, or 61. Although there is a high degree of similarity among the isoforms, K-Ras mutations are far more frequently observed in cancer, and each isoform displays preferential coupling to particular cancer types. We examined the mutational spectra of Ras isoforms curated from large-scale tumor profiling and found that each isoform exhibits surprisingly distinctive codon mutation and amino-acid substitution biases. These findings were unexpected given that these mutations occur in regions that share 100% amino-acid sequence identity among the 3 isoforms. Of importance, many of these mutational biases were not due to differences in exposure to mutagens, because the patterns were still evident when compared within specific cancer types. We discuss potential genetic and epigenetic mechanisms, as well as isoform-specific differences in protein structure and signaling, that may promote these distinct mutation patterns and differential coupling to specific cancers. Cancer Res; 72(10); 2457–67. ©2012 AACR.
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“Approximately 90% of PDAC cases harbor a Kirsten rat sarcoma (KRAS) mutation (Prior et al., 2012).”
From The antitumoral effect of statins in pancreatic ductal adenocarcinoma: a scoping review (2026) · cites this paper as Prior et al., 2012
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“This specific mutation, present in ~3% of CRC cases, 2 is associated with significantly reduced progression-free survival (PFS) and overall survival (OS) compared to KRAS wildtype tumors.[3][4][5]”
From Garsorasib, a KRAS G12C inhibitor, with or without cetuximab, an EGFR antibody, in colorectal cancer cohorts of a phase II trial in advanced solid tumors with KRAS G12C mutation (2025) · cites this paper as [2]
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“Unlike other clinically actionable genomic alterations found in NSCLCs (such as EGFR and ALK aberrations), KRAS mutations, particularly KRASG12C and KRASG12V, are strongly associated with smoking29–31.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [29]
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“However, RAS mutations and the resulting deregulated signaling events are responsible for one third of all human cancers4 (Figure 1).”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [4]
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“Overall, KRAS is mutated in many cancers (predominantly adenocarcinomas), whereas NRAS mutations are prominent in melanoma and myeloid cancer4,15,16 (Fig. 1).”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [4]
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“The basis of the specific G12X mutation frequencies has remained unclear, except for the G12C transversion mutation (c.34G>T) associated with smoking in lung cancer [6,7].”
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BackgroundState-selective modulation of heterotrimeric Gαs signaling with macrocyclic peptides
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“KRAS mutations are mainly represented by single-base missense mutations, almost all clustering in three hotspots at codon 12, 13, and 61 (10,11).”
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“Aberrant Ras mutations or post translational modifications lead to the dysfunction of ‘ON’-‘OFF’ control on Ras effectors, resulting in cancers as well as a collection of developmental conditions called ‘‘ RASopathies ” [3,8–10].”
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“[7–9] Indeed, RAS mutations are responsible for the abolishment of the GAP-induced GTP hydrolysis of RAS, thereby leading to the maintenance of the GTP-bound active form of the protein [10,11] or for the impairment of the active site conformation and consequently of the intrinsic hydrolysis activity.”
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Self-citation“Pathway drug cocktail”: targeting Ras signaling based on structural pathways
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“athway [18]. Although oncogenic mutations in residues other than G12, G13 and Q61 are rare (Box 2), several human tumors contain mutations in K-Ras or N-Ras switch II, helix 3 and the allosteric site [23]. Prominent examples are the two arginines depicted in Figure 4b. Human tumors with R68S in K-Ras and R68T in N-Ras…”
BackgroundSelf-citationOvercoming Resistance to Drugs Targeting KRAS Mutation
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“Ras signaling pathways are tightly regulated in normal cells and malignant transformation occurs when Ras proteins are constitutively activated.(1,29,30) Inmost cases, themutations ofRASgenes in tumor cells confers resistance to GAPs-mediated GTP hydrolysis, locking Ras protein in its active state that favors tumor gr…”
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“G12S HRAS somatic mutation has been mainly observed in upper aerodigestive tract malignancies [33].”
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“According to several studies, hotspots of RAS mutations have been identified in codons 12, 13, 59, 61, 117, and 146, which are considered to induce conformational changes into constitutively active forms (Prior et al., 2012; Smith et al., 2010).”
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Targeting Ras-Driven Cancer Cell Survival and Invasion through Selective Inhibition of DOCK1
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“Accumulating evidence indicates that mutations activating RAS family members, K-RAS, H-RAS, and N-RAS, are found in 20%–30% of human tumors (Cox et al., 2014; Prior et al., 2012; Spiegel et al., 2014), thereby placing thesemutations as major drivers of cancers.”
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“M in RAS have been found in >80% of cancer indications (1, 2) with the majority occurring in KRAS (3).”
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“G12V with PIP2 doped DOPC lipid vesicles without (red) and with (green) Gd3+ spin-labeled lipid.”
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“This site cycles between the guanosine diphosphate (GDP)-bound inactive and the guanosine-5′-triphosphate (GTP)-bound active forms.”
BackgroundInfluentialK-Ras prenylation as a potential anticancer target
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“These mutations impair the ability of GAP proteins to facilitate hydrolyses of GTP to GDP, and therefore the proteins will be constitutively in active, GTP-bound state [1].”
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“The first TSAs targeted by therapeutic cancer vaccines arose from RAS mutations, which are the most common somatic mutations in human cancer (26).”
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“We established a non-cancer colon NCM460 cell model to study, in the same genetic background, the effect of overexpressing three of the most common mutant KRAS alleles that occur in CRCs: KRASG13D, KRASG12D and KRASG12V [35].”
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“In tumors that are Ras-transformed, the requirement for amino acids can be met by significantly increased macropinocytic uptake of proteins, with the most abundant serum protein, albumin, playing an important role as a nutrient source [2, 3].”
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“The KRAS gene consists of 6 exons on chromosome 12 (8, 27).”
BackgroundYasuda, T., Ueno, T., Fukumura, K., Yamato, A., Ando, M., Yamaguchi, H., Soda, M., Kawazu, M., Sai, E., Yamashita, Y., et al. (2013) · Leukemia · doi:10.1038/leu.2013.278 · Cited by 61
The Ras–Membrane Interface: Isoform-Specific Differences in the Catalytic Domain
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“K-Ras is by far the most oncogenic isoform, showing extensive prominence in pancreatic and colorectal cancers, while melanomas have a high incidence of N-Ras mutations (5).”
BackgroundInfluentialSelf-citationEvaluation of the selectivity and sensitivity of isoform- and mutation-specific RAS antibodies
Waters, A. M., Ozkan‐Dagliyan, I., Vaseva, A. V., Fer, N. D., Strathern, L. A., Hobbs, G. A., Tessier‐Cloutier, B., Gillette, W., Bagni, R., Whiteley, G., et al. (2017) · Science Signaling · doi:10.1126/scisignal.aao3332 · Cited by 62
“In striking contrast, Q61 is the predominant mutational hotspot in NRAS (62%), followed by G12 (23%), and then G13 (12%).”
BackgroundInfluentialPotentiation of Kras peptide cancer vaccine by avasimibe, a cholesterol modulator
Pan, J., Zhang, Q., Palen, K. A., Wang, L., Qiao, L., Johnson, B. D., Sei, S., Shoemaker, R. H., Lubet, R. A., Wang, Y., et al. (2019) · EBioMedicine · doi:10.1016/j.ebiom.2019.10.044 · Cited by 61
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“Yet, there has been moderate success for small molecules designed to covalently target the G12C oncogenic mutation in Ras, especially important for the goal of selectively targeting prominent mutations linked to specific cancer types, in this case lung adenocarcinoma (Prior et al. 2012).”
BackgroundMethodSelf-citationVähätupa, M., Järvinen, T. A. H., & Uusitalo‐Järvinen, H. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.00873 · Cited by 61
Laçin, Ş., Rashid, A., Chun, Y. S., Odisio, B. C., Koay, E. J., Abdel‐Wahab, R., & Kaseb, A. O. (2019) · Springer eBooks · doi:10.1007/978-3-030-18890-0_13 · Cited by 60
Chen, L., Zhang, Y., Cheng, Y., Zhang, D., Zhu, S., & Ma, X. (2018) · Gene · doi:10.1016/j.gene.2018.09.029 · Cited by 60
Artemisinin inhibits NRas palmitoylation by targeting the protein acyltransferase ZDHHC6
Qiu, N., Abegg, D., Guidi, M., Gilmore, K. M., Seeberger, P. H., & Adibekian, A. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.07.012 · Cited by 61
Cross‐Talk between Oxidative Stress and m6A RNA Methylation in Cancer
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Liu, Z., Filip, I., Gómez, K., Engelbrecht, D., Meer, S., Lalloo, P. N., Patel, P., Perner, Y., Zhao, J., Wang, J., et al. (2020) · Blood Cancer Discovery · doi:10.1158/2643-3230.bcd-20-0051 · Cited by 59
Shen, Y. L., Chen, J.-Q., & Li, X. (2024) · Genes & Diseases · doi:10.1016/j.gendis.2024.101374 · Cited by 73
“18 Among them, the KRAS G12C mutation is the most common, accounting for over 50% of KRAS mutations.”
Sheffels, E., Sealover, N. E., Wang, C., Kim, D., Vazirani, I. A., Lee, E., Terrell, E. M., Morrison, D. K., Luo, J., & Kortum, R. L. (2018) · Science Signaling · doi:10.1126/scisignal.aar8371 · Cited by 56
“DISCUSSION Driver mutations in the RAS family of GTPases occur in ~30% of human tumors (38, 39).”
BackgroundRen, X., Santhosh, S. M., Coppo, L., Ogata, F. T., Lu, J., & Holmgren, A. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2019.01.037 · Cited by 59
Uncovering a membrane-distal conformation of KRAS available to recruit RAF to the plasma membrane
Van, Q. N., López, C. A., Tonelli, M., Taylor, T. E., Niu, B., Stanley, C. B., Bhowmik, D., Tran, T. H., Frank, P. H., Messing, S. A. J., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2006504117 · Cited by 58
“KRAS is the most frequently mutated isoform, as it is identified in 60% of pancreatic, 33% of colorectal, and 17% of lung cancers (1).”
BackgroundZhou, Z.-W., Ambrogio, C., Bera, A. K., Li, Q., Li, X.-X., Li, L., Son, J., Gondi, S., Li, J., Campbell, E., et al. (2020) · Cancer Research · doi:10.1158/0008-5472.can-20-0448 · Cited by 60
“Most oncogenic RAS mutations occur at codons 12, 13, and 61 (1).”
BackgroundMethodInfluentialGraded inhibition of oncogenic Ras-signaling by multivalent Ras-binding domains
Augsten, M., Böttcher, A., Spanbroek, R., Rubio, I., & Friedrich, K. (2014) · Cell Communication and Signaling · doi:10.1186/1478-811x-12-1 · Cited by 57
“Mutations that convert Ras into an oncoprotein are found in up to 25% of human tumors [15] (www.”
BackgroundMSEA: detection and quantification of mutation hotspots through mutation set enrichment analysis
Jia, P., Wang, Q., Chen, Q., Hutchinson, K. E., Pao, W. J., & Zhao, Z. (2014) · Genome biology · doi:10.1186/preaccept-1822061407140231 · Cited by 58
Quantification of spatiotemporal patterns of Ras isoform expression during development
Newlaczyl, A. U., Coulson, J. M., & Prior, I. A. (2017) · Scientific Reports · doi:10.1038/srep41297 · Cited by 59
Self-citationMcCormick, F. P. (2018) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-050216-122010 · Cited by 58
“This tail binds calmodulin (Villalonga et al. 2001), is phosphorylated by PKC (Sung et al. 2013), and confers stem-like functions on KRAS4B (Quinlan et al. 2008, Wang et al. 2015).”
BackgroundCodon usage regulates human KRAS expression at both transcriptional and translational levels
Fu, J., Dang, Y., Counter, C. M., & Liu, Y. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.004908 · Cited by 60
“The importance of the low expression of KRAS cannot be overstated, as this gene is essential (10), unlike NRAS and HRAS, and is mutated in one quarter of all human cancers, far more than the other two RAS genes (4).”
BackgroundUsing macropinocytosis for intracellular delivery of therapeutic nucleic acids to tumour cells
Desai, A. S., Hunter, M. R., & Kapustin, A. N. (2018) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2018.0156 · Cited by 58
Germline-Activating RRAS2 Mutations Cause Noonan Syndrome
Niihori, T., Nagai, K., Fujita, A., Ohashi, H., Okamoto, N., Okada, S., Harada, A., Kihara, H., Arbogast, T., Funayama, R., et al. (2019) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2019.04.014 · Cited by 58
“Gln72His has been found in endometrioid carcinoma and is likely pathogenic because of its homologous position to the hotspot Gln61 in KRAS, NRAS, and HRAS.(16) Our functional data agree with that prediction.”
BackgroundInfluentialFerino, A., Nicoletto, G., D’Este, F., Zorzet, S., Lago, S., Richter, S. N., Tikhomirov, A. S., Shchekotikhin, A. E., & Xodo, L. E. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01577 · Cited by 60
Oncogenic mutant RAS signaling activity is rescaled by the ERK/MAPK pathway
Gillies, T. E., Pargett, M., Silva, J. M., Teragawa, C., McCormick, F. P., & Albeck, J. G. (2020) · Molecular Systems Biology · doi:10.15252/msb.20209518 · Cited by 54
“All KRAS mutant cell lines, as well as HRASWT, exhibited significantly elevated baseline ERK activity compared to KRASWT, with the highest levels observed in KRASQ61R and KRASG12C.”
BackgroundInfluentialYang, H., Liang, S.-Q., Xu, D., Yang, Z., Marti, T. M., Gao, Y., Kocher, G. J., Zhao, H., Schmid, R. A., & Peng, R.-W. (2019) · Oncogenesis · doi:10.1038/s41389-019-0158-7 · Cited by 58
Intrinsic protein disorder in oncogenic KRAS signaling
Nussinov, R., Jang, H., Tsai, C., Liao, T.-J., Li, S., Fushman, D., & Zhang, J. (2017) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-017-2564-3 · Cited by 58
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Raf promotes dimerization of the Ras G-domain with increased allosteric connections
Packer, M. R., Parker, J. A., Chung, J. K., Li, Z., Lee, Y. K., Cookis, T., Guterres, H., Alvarez, S. A., Hossain, M. A., Donnelly, D. P., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2015648118 · Cited by 55
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“NSCLC, is identified in 20% to 30% of lung adenocarcinomas.(6,7) Although extensively studied, the prognostic value of KRAS MUTs remains unclear.”
BackgroundThe Plasma Membrane as a Competitive Inhibitor and Positive Allosteric Modulator of KRas4B Signaling
Neale, C., & García, A. E. (2020) · Biophysical Journal · doi:10.1016/j.bpj.2019.12.039 · Cited by 56
Non-small cell lung cancer: Emerging molecular targeted and immunotherapeutic agents
Singh, T., Hassanabad, M. F., & Hassanabad, A. F. (2021) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2021.188636 · Cited by 54
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“58,59 Mutations of RAS proteins alone appear in a larger fraction of all human cancers diagnosed in the US, 60 − 62 rendering RAS an attractive therapeutic target.”
The impact of the BCR-ABL oncogene in the pathology and treatment of chronic myeloid leukemia
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Endometrial Carcinoma: Specific Targeted Pathways
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“Notable exceptions are, for example, K-Ras mutations, which are present in approximately 60% of pancreatic carcinomas and 20% of all cancers [11].”
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Tipifarnib in recurrent, metastatic HRAS‐mutant salivary gland cancer
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Rab34 GTPase mediates ciliary membrane formation in the intracellular ciliogenesis pathway
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Metadata
- Authors
- Prior, I. A., Lewis, P. D., & Mattos, C.
- Affiliations
- Northeastern University (US)
- Corresponding author
- Prior, Ian A.
- Venue
- Cancer Research
- Published
- 2012-05-14
- Volume
- 72
- Issue
- 10
- Pages
- 2457-2467
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC3354961
- OpenAlex
- W2135184154
- Cited by
- 2,063
- References
- 67
- Citations by year
- 2026: 114 · 2025: 154 · 2024: 169 · 2023: 203 · 2022: 189 · 2021: 223 · 2020: 203 · 2019: 164 · 2018: 162 · 2017: 144 · 2016: 110 · 2015: 111 · 2014: 52 · 2013: 47 · 2012: 13
- FWCI
- 23.60
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Wellcome Trust (067398)
- Cancer Research UK (A6672)
- Biotechnology and Biological Sciences Research Council (BB/G018162/1)
- National Cancer Institute (R56CA096867)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- RAS mutations, KRAS, H-Ras, NRAS, Ras isoforms, codon 12 mutation, mutational spectra, carcinogenesis, epigenetic mechanisms, Ras signaling
- MeSH terms
- Cell Transformation, Neoplastic, Codon, Humans, Models, Molecular, Molecular Conformation, Neoplasms, Genes, ras, Signal Transduction, Point Mutation, ras Proteins, Protein Isoforms, Catalytic Domain, Databases, Genetic, Epigenesis, Genetic
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