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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]
In the citing paper
“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]
In the citing paper
“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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“In the case of NRAS and HRAS, pTyr32 also concomitantly enhanced GAP association and GTP hydrolysis (Bunda, et al., 2014).”
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BackgroundEnhancing anticancer activity of checkpoint immunotherapy by targeting RAS
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“which drive multiple aspects of malignant transformation and progression.(1) Mutations in the KRAS isozyme are the most frequent of all cancers with RAS mutations.”
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“inhibitors of KRAS G12C mutant that is most prevalent in non-small cell lung cancer and lung adenocarcinomas [29], in which presence of KRASmutations mean worse prognosis, and elevated resistance for certain therapies [30–32].”
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“There is increasing evidence that Ras proteins have isoform-specific biological functions and tumorigenic effects, possibly attributed to the C-terminal hypervariable region, and that different mutation codons might induce different transformation potentials.(11) Different tumor types often display specificity in RAS…”
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“Hyperactivation of this pathway, caused by gene amplifications, chromosomal abnormalities, or mutations, is among the most common oncogenic events in human cancer (Fern´andez-Medarde and Santos, 2011; Prior et al., 2012).”
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“On the other hand, several oncogenic mutations occurring in BRAF , NRAS , HRAS, and KRAS implicate constitutive MAPK pathway activity, resulting in hyperproliferative developmental disorder and tumorigenesis [20,21].”
A computationally engineered RAS rheostat reveals RAS–ERK signaling dynamics
Rose, J. C., Huang, P., Camp, N. D., Ye, J., Leidal, A. M., Goreshnik, I., Trevillian, B. M., Dickinson, M. S., Cunningham‐Bryant, D., Debnath, J., et al. (2016) · Nature Chemical Biology · doi:10.1038/nchembio.2244 · Cited by 26
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Anti-helminthic niclosamide inhibits Ras-driven oncogenic transformation via activation of GSK-3
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“Importantly, the destruction motif of Ras is located on the C-terminus while the mutational hot spot in human cancer is on the N-terminus [11, 24], providing an alternative approach to suppressing mutant Ras by modulation of GSK-3 (Figure 1C).”
BackgroundActivating Mutations in PTPN11 and KRAS in Canine Histiocytic Sarcomas
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“Mutations in KRAS are present in 22% of all human cancers, and known to be activators of MAPK signaling [43].”
BackgroundPrognostic Role of KRAS mRNA Expression in Breast Cancer
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“Other studies have also reported rare frequencies of KRAS mutation in invasive breast cancers [5,29].”
BackgroundTherapeutic targeting of protein S-acylation for the treatment of disease
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“In humans, the genes HRAS, NRAS and KRAS encode three closely related proteins that are frequently mutated in cancer, the most common of which is K-RAS (86% of all RAS mutant cancers) with smaller contributions from NRAS (11%) and H-RAS (3%), that play a pivotal role in driving unregulated cell growth [51, 57-58].”
BackgroundHead perturbations during walking while viewing a head-fixed target.
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Driver Mutations in Pancreatic Cancer and Opportunities for Targeted Therapy
Olaoba, O. T., Adelusi, T. I., Yang, M. J., Maidens, T., Kimchi, E. T., Staveley-O’Carroll, K. F., & Li, G. (2024) · Cancers · doi:10.3390/cancers16101808 · Cited by 28
“It is the most mutated gene in all of the Ras family and therefore drives oncogenesis in most cancer cells [24,25]. is the most mutated gene in all of the Ras family and therefore drives oncogenesis in most cancer cells [24,25].”
BackgroundCurrent status of the development of Ras inhibitors
Shima, F., Matsumoto, S., Yoshikawa, Y., Kawamura, T., Isa, M., & Kataoka, T. (2015) · The Journal of Biochemistry · doi:10.1093/jb/mvv060 · Cited by 28
“Because the absence of such a pocket in the state 2 structures had rendered Ras ‘undruggable’, our discovery of the ‘druggable’ pocket shed a light on the structure-based drug design (SBDD) of specific inhibitors that allosterically block Ras activation by stabilizing the inactive state 1 conformation (28, 29).”
Ni, D., Liu, D., Zhang, J., & Lu, S. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19010151 · Cited by 26
Overcoming Resistance to Therapies Targeting the MAPK Pathway in BRAF-Mutated Tumours
Paton, E. L., Turner, J. A., & Schlaepfer, I. R. (2020) · Journal of Oncology · doi:10.1155/2020/1079827 · Cited by 28
“Constitutive activation of the MAPK pathway, through overstimulation of receptors, RAS activation, or uncontrolled kinase activity, drives many human cancers [32].”
BackgroundSalmonella-based platform for efficient delivery of functional binding proteins to the cytosol
Chabloz, A., Schaefer, J. V., Kozieradzki, I., Cronin, S. J. F., Strebinger, D., Macaluso, F., Wald, J., Rabbitts, T. H., Plückthun, A., Marlovits, T. C., et al. (2020) · Communications Biology · doi:10.1038/s42003-020-1072-4 · Cited by 26
A perspective on the early days of RAS research
Weiss, R. A. (2020) · Cancer and Metastasis Reviews · doi:10.1007/s10555-020-09919-1 · Cited by 28
Dynamically encoded reactivity of Ras enzymes: opening new frontiers for drug discovery
Pálfy, G., Menyhárd, D. K., & Perczel, A. (2020) · Cancer and Metastasis Reviews · doi:10.1007/s10555-020-09917-3 · Cited by 26
Lu, H., & Martı́, J. (2020) · The Journal of Physical Chemistry Letters · doi:10.1021/acs.jpclett.0c02809 · Cited by 21
Durrant, D., Smith, E. A., Goncharova, E. I., Sharma, N. D., Alexander, P., Stephen, A. G., Henrich, C. J., & Morrison, D. K. (2021) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-21-0175 · Cited by 25
“Mutant KRAS and full-length, wild-type (WT) CRAF were selected as the BRET pair, given that KRAS is the RAS family member most frequently mutated in human cancer (3) and that our previous BRET analysis revealed that mutant KRAS produces the strongest BRET signal when paired with CRAF (11).”
BackgroundMethodKumar, S. U., & Doss, C. G. P. (2021) · Computers in Biology and Medicine · doi:10.1016/j.compbiomed.2021.104946 · Cited by 26
Metabolic synthetic lethality by targeting NOP56 and mTOR in KRAS-mutant lung cancer
Zhang, Y., Liang, S., Zhao, L., Yang, H., Marti, T. M., Hegedűs, B., Gao, Y., Zheng, B., Chen, C., Wang, W., et al. (2022) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-022-02240-5 · Cited by 28
“RAS-driven cancers, particularly pancreatic, colon, and non-small cell lung cancer (NSCLC) [1].”
BackgroundInfluentialMulti-Omic Approaches in Colorectal Cancer beyond Genomic Data
Sardo, E., Napolitano, S., Corte, C. M. D., Ciardiello, D., Raucci, A., Arrichiello, G., Troiani, T., Ciardiello, F., Martinelli, E., & Martini, G. (2022) · Journal of Personalized Medicine · doi:10.3390/jpm12020128 · Cited by 27
“V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) is mutated in 40% of CRC cases, mostly in exon 2, (codons 12 and 13) and less frequently in exon 3 (codon 61) and exon 4 (codon 146), followed by NRAS, which is present in approximately 3–5% of CRC and can be found in exon 3 (codon 61) and exon 2 (codons 12,…”
BackgroundEngaging the Lysosome and Lysosome-Dependent Cell Death in Cancer
Berg, A. L., Rowson-Hodel, A. R., Wheeler, M. R., Hu, M., Free, S. R., & Carraway, K. L. (2022) · Exon Publications eBooks · doi:10.36255/exon-publications-breast-cancer-lysosome · Cited by 26
“These data suggest that aSMase inhibition may not only be cancer cell specific (29), but may also be particularly well suited for K-Ras-driven cancers (i.e., pancreas, colon and lung), which currently lack targeted therapeutic options (297).”
Multiple Strategies to Develop Small Molecular KRAS Directly Bound Inhibitors
Zhou, X., Ji, Y., & Zhou, J. (2023) · Molecules · doi:10.3390/molecules28083615 · Cited by 27
“; it is found in one out of every seven human cancers [1,2].”
BackgroundChemical Biology Tools for Regulating RAS Signaling Complexity in Space and Time
van Hattum, H., & Waldmann, H. (2014) · Chemistry & Biology · doi:10.1016/j.chembiol.2014.08.001 · Cited by 27
Li, Y., Takahashi, M., & Stork, P. A. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.463067 · Cited by 26
“Indeed, oncogenic Rasmutations are present in nearly 30%of human tumors (1, 2).”
BackgroundOncogenic K-ras confers SAHA resistance by up-regulating HDAC6 and c-myc expression
Wang, Q., Tan, R., Zhu, X. J., Zhang, Y., Tan, Z., Su, B., & Li, Y. (2016) · Oncotarget · doi:10.18632/oncotarget.7134 · Cited by 25
“K-ras is commonly mutated at codon 12 or 13 [19, 20].”
BackgroundThe spatiotemporal regulation of RAS signalling
Herrero, A., Matallanas, D., & Kölch, W. (2016) · Biochemical Society Transactions · doi:10.1042/bst20160127 · Cited by 26
Drosten, M., Simón-Carrasco, L., Hernández-Porras, I., Lechuga, C. G., Blasco, M. T., Jacob, H. K. C., Fabbiano, S., Potenza, N., Bustelo, X. R., Guerra, C. E., et al. (2016) · Cancer Research · doi:10.1158/0008-5472.can-16-2925 · Cited by 26
Stephens, R. M., Yi, M., Kessing, B. D., Nissley, D. V., & McCormick, F. P. (2017) · Cancer Informatics · doi:10.1177/1176935117711944 · Cited by 26
El-Refai, S. M., Brown, J. D., Arnold, S. M., Black, E. P., Leggas, M. L., & Talbert, J. (2017) · JCO Clinical Cancer Informatics · doi:10.1200/cci.17.00010 · Cited by 27
“However, our results did not show an effect in colorectal cancer, which also has a high frequency of KRAS mutation.(62) Statin use after diagnosis was shown previously to reduce colorectal cancer–specific mortality,(11) and the prospective use of simvastatin with cetuximab plus irinotecan in patients with KRAS mutatio…”
BackgroundResultChae, Y. K., Arya, A., Chiec, L. S., Shah, H. A., Rosenberg, A. J., Patel, S. P., Raparia, K., Choi, J., Wainwright, D. A., Villaflor, V. M., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.19809 · Cited by 31
Ferris, L. K., Moy, R. L., Gerami, P., Sligh, J. E., Jansen, B., Yao, Z., & Cockerell, C. J. (2018) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2018.10.041 · Cited by 26
“These early hotspot driver mutations in BRAF, NRAS, and especially TERT, not only correlate with adverse histopathologic criteria, but are found in early and persist in late stage disease, identifying risk of aggressive tumor behavior with metastasis and poor prognosis (Griewank et al., 2014; Liu et al., 2016; Nagore…”
BackgroundTranslating current basic research into future therapies for neurofibromatosis type 1
Brosseau, J., Liao, C.-P., & Le, L. Q. (2020) · British Journal of Cancer · doi:10.1038/s41416-020-0903-x · Cited by 26
Bioactive atropisomers: Unraveling design strategies and synthetic routes for drug discovery
Liu, S., Zhao, Q., Liu, X., Gamble, A. B., Huang, W., Yang, Q., & Han, B. (2024) · Medicinal Research Reviews · doi:10.1002/med.22037 · Cited by 29
Galectin‐8 inhibition and functions in immune response and tumor biology
Purić, E., Nilsson, U. J., & Anderluh, M. (2024) · Medicinal Research Reviews · doi:10.1002/med.22041 · Cited by 29
“142 K ‐ Ras produces two splice variants, a minor K ‐ Ras4A variant and a major variant K ‐ Ras4B.”
Translational Advances in Oncogene and Tumor-Suppressor Gene Research
Stojchevski, R., Sutanto, E. A., Sutanto, R., Hadzi‐Petrushev, N., Mladenov, M. I., Singh, S. P., Sinha, J. K., Ghosh, S., Yarlagadda, B., Singh, D. K. K., et al. (2025) · Cancers · doi:10.3390/cancers17061008 · Cited by 34
Oncogenic RAC1 and NRAS drive resistance to endoplasmic reticulum stress through MEK/ERK signalling
Bright, M. D., Clarke, P. A., Workman, P., & Davies, F. E. (2018) · Cellular Signalling · doi:10.1016/j.cellsig.2018.01.004 · Cited by 25
“It has been estimated that one third of all cancers contain an upregulated MAPK signalling pathway [38] and around 16% of all cancers contain a RAS mutation [39].”
BackgroundPan, J., Zheng, Q., Li, Y., Yu, L.-L., Wu, Q.-W., Zheng, J.-Y., Pan, X.-J., Xie, B.-S., Wu, Y.-A., Qian, J. X., et al. (2019) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-18-1269 · Cited by 25
“HRas, a small GTPase, is a member of the Ras oncogene family, whose mutations are responsible for the development of bladder cancer, thyroid cancer, salivary ductal carcinoma, epithelial– myoepithelial carcinoma, and renal cancer (16, 17).”
BackgroundLiu, Z., Wang, M., Wang, H., Fang, L., & Gou, S. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112269 · Cited by 25
Small molecule inhibitors of RAS proteins with oncogenic mutations
Orgován, Z., & Keserű, G. M. (2020) · Cancer and Metastasis Reviews · doi:10.1007/s10555-020-09911-9 · Cited by 25
“The distribution among isoforms and the frequency differs across different cancer types [18].”
BackgroundMcFall, T. B., Schomburg, N. K., Rossman, K. L., & Stites, E. C. (2020) · Cell Communication and Signaling · doi:10.1186/s12964-020-00645-3 · Cited by 26
Maru, Y., Tanaka, N., Tatsumi, Y., Nakamura, Y., Itami, M., & Hippo, Y. (2021) · Oncogenesis · doi:10.1038/s41389-021-00337-8 · Cited by 25
“Although Ras activation is normally regulated through GTPbinding and degradation in a transient and reversible manner, its constitutive activation is often observed in various types of cancer, mostly by missense mutations in the GTP-binding sites at codons 12, 13, and 61 or by gene amplification [2].”
BackgroundPan-RAS inhibitors: Hitting multiple RAS isozymes with one stone
Coley, A. B., Ward, A., Keeton, A. B., Chen, X., Maxuitenko, Y. Y., Prakash, A., Li, F., Foote, J. B., Buchsbaum, D. J., & Piazza, G. A. (2022) · Advances in cancer research · doi:10.1016/bs.acr.2021.07.009 · Cited by 23
Stabilization of the RAS:PDE6D Complex Is a Novel Strategy to Inhibit RAS Signaling
Yelland, T., García, E., Parry, C., Kowalczyk, D., Wojnowska, M., Gohlke, A., Zalar, M., Cameron, K., Goodwin, G., Yu, Q., et al. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c01265 · Cited by 25
Genetic alterations shaping tumor response to anti-EGFR therapies
Vaquero, J., Pavy, A., Gonzalez‐Sanchez, E., Meredith, M., Arbelaiz, A., & Fouassier, L. (2022) · Drug Resistance Updates · doi:10.1016/j.drup.2022.100863 · Cited by 26
Hu, Z., & Martí, J. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232213865 · Cited by 25
Leveraging Molecular and Immune-Based Therapies in Leptomeningeal Metastases
Wilcox, J. A., & Boire, A. A. (2022) · CNS Drugs · doi:10.1007/s40263-022-00975-5 · Cited by 25
“KRAS, together with other RAS isoforms (HRAS and NRAS), are among the most commonly mutated proteins in cancer biology, present in 90% of pancreatic cancers, 42% of colon cancers, 20% of lung cancers, and 20% of melanoma [100, 101].”
BackgroundEpitranscriptic regulation of HRAS by N 6 -methyladenosine drives tumor progression
Pan, Y., Gu, Y., Liu, T., Zhang, Q., Yang, F., Duan, L., Cheng, S., Zhu, X., Xi, Y., Chang, X., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2302291120 · Cited by 25
“Among which, KRAS is the most frequently mutated, while HRAS is the less in all cancer-associated RAS mutations (3, 4).”
BackgroundRAS‐targeted cancer therapy: Advances in drugging specific mutations
Liu, C., Ye, D., Yang, H., Chen, X., Su, Z., Li, X., Ding, M., & Liu, Y. (2023) · MedComm · doi:10.1002/mco2.285 · Cited by 25
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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