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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]
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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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Re-engineering the Pancreas Tumor Microenvironment: A "Regenerative Program" Hacked
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“Mutations that directly activate one of the three members of the Ras family (K, N, and H-Ras) are causally implicated in some 25% of all human tumors, and as many as 90% of PDACs, whereas indirect activation of Ras signaling by mutations in upstream Ras effectors or downstream effectors is implicated in most of the re…”
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“…cancer, 39% of CRC, 30% of cancer of biliary tract, 17% of non-small-cell lung cancer (NSCLC), 15% of ovarian cancer, 15% of endometrium cancer, and 23% of blood cancer (Sanger Institute Cosmic Database) (Fern (cid:1) andez-Medarde and Santos, 2011; Forbes et al ., 2011; Prior et al ., 2012).”
An engineered chimeric toxin that cleaves activated mutant and wild-type RAS inhibits tumor growth
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“Different isoforms of Ras (HRas, KRas, and NRas) have high overall sequence identity and are the most commonly mutated of all discovered oncogenes (5, 6).”
BackgroundInsight into the mechanism of allosteric activation of PI3Kα by oncoprotein K-Ras4B
Li, X., Dai, J., Ni, D., He, X., Zhang, H., Zhang, J., Fu, Q., Liu, Y., & Lu, S. (2019) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2019.12.020 · Cited by 39
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“The G12C is the highest KRAS mutation in NSCLC [6], while the G12D is the highest KRAS mutation in colorectal cancer [4].”
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“They may represent up to 30% of lung cancer in the Caucasian smoking population [4], with 80% of them are specifically altered in codon12 [5].”
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“INTRODUCTION RAS mutations were some of the first identified acquired genetic causes of cancer and are common in many forms of malignancy, particularly gastrointestinal, skin, and lung cancers (Prior et al., 2012).”
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“1%) (Table 1), which is consistent with the most common mutations identified through somatic testing of pancreatic adenocarcinoma tumors [39].”
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“It is associated with hyperproliferation and cancer [94].”
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A new regulatory mechanism for Raf kinase activation, retinoic acid-bound Crabp1
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Behind the Wheel of Epithelial Plasticity in KRAS-Driven Cancers
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“Oncogenic KRAS RAS genes (HRAS, KRAS, and NRAS) are the most frequently mutated gene family in cancer (106).”
BackgroundGenetic profile of advanced thyroid cancers in relation to distant metastasis
Song, E., Song, D. E., Ahn, J., Kim, T. Y., Kim, W. B., Shong, Y. K., Jeon, M. J., & Kim, W. G. (2020) · Endocrine Related Cancer · doi:10.1530/erc-19-0452 · Cited by 38
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“NRAS-mutated tumors are less common than KRAS-mutated malignancies and are found in approximately 8% of human cancers (3, 4).”
BackgroundMethodClinical and Preclinical Outcomes of Combining Targeted Therapy With Radiotherapy
Elbanna, M., Chowdhury, N. N., Rhome, R. M., & Fishel, M. L. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.749496 · Cited by 44
Design, synthesis and biological evaluation of KRASG12C-PROTACs
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The RAS-RAL axis in cancer: evidence for mutation-specific selectivity in non-small cell lung cancer
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D‐1553: A novel KRASG12C inhibitor with potent and selective cellular and in vivo antitumor activity
Shi, Z., Weng, J., Niu, H., Yang, H., Liu, R., Weng, Y., Zhu, Q., Zhang, Y., Tao, L., Wang, Z., et al. (2023) · Cancer Science · doi:10.1111/cas.15829 · Cited by 38
The Genetic Analysis and Clinical Therapy in Lung Cancer: Current Advances and Future Directions
Rina, A., Maffeo, D., Minnai, F., Esposito, M., Palmieri, M., Serio, V. B., Rosati, D., Mari, F., Frullanti, E., & Colombo, F. (2024) · Cancers · doi:10.3390/cancers16162882 · Cited by 44
“Mutations in the KRAS gene are among the most common genetic alterations in lung cancers, particularly in NSCLC [56,57].”
BackgroundPerturbomics: CRISPR–Cas screening-based functional genomics approach for drug target discovery
Park, B.-S., Lee, M., Kim, J. Y., & Kim, T. (2025) · Experimental & Molecular Medicine · doi:10.1038/s12276-025-01487-0 · Cited by 41
“For example, cancers often exhibit mutations in hard-to-drug onco-genes such as KRAS 20 or loss of tumor suppressors such as PTEN 21 , creating an urgent need for novel therapeutic strategies.”
Liu, S., Gao, A., Zhang, B., Zhang, Z., Zhao, Y., Chen, P., Ji, M., Hou, P., & Shi, B. (2014) · Experimental and Molecular Pathology · doi:10.1016/j.yexmp.2014.08.005 · Cited by 37
Structural Dynamics in Ras and Related Proteins upon Nucleotide Switching
Harrison, R. A., Lu, J., Carrasco, M. A., Hunter, J., Manandhar, A., Gondi, S. R., Westover, K. D., & Engen, J. R. (2016) · Journal of Molecular Biology · doi:10.1016/j.jmb.2016.10.017 · Cited by 37
“Such Ras mutations are present in 20–30% of all human tumor types, and over 90% of tumors for certain diseases such as pancreatic cancer [6, 31].”
BackgroundTargeting MEK in a Translational Model of Histiocytic Sarcoma
Takada, M., Hix, J. M. L., Corner, S. M., Schall, P. Z., Kiupel, M., & Yuzbasiyan‐Gurkan, V. (2018) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-17-1273 · Cited by 37
“Mutations in KRAS are present in 22% of all cancers (58), with 82.”
BackgroundWang, K., Baldwin, G. S., Nikfarjam, M., & He, H. Z. (2018) · World Journal of Gastroenterology · doi:10.3748/wjg.v24.i33.3709 · Cited by 37
Approaches to inhibiting oncogenic K-Ras
Gorfe, A. A., & Cho, K. (2019) · Small GTPases · doi:10.1080/21541248.2019.1655883 · Cited by 36
“GTPase activity of Ras due to somatic mutations, typically at codons 12, 13 and 61, is associated with 15–20% of all human cancers, and K-Ras mutations account for 85% of all Ras mutations [4,7,8].”
BackgroundTargeting RAS phosphorylation in cancer therapy: Mechanisms and modulators
Qiu, Y., Wang, Y., Chai, Z., Ni, D., Li, X., Pu, J., Chen, J., Zhang, J., Lu, S., Lv, C., et al. (2021) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2021.02.014 · Cited by 39
Prognostic and therapeutic impact of the KRAS G12C mutation in colorectal cancer
Qunaj, L., May, M. S., Neugut, A. I., & Herzberg, B. O. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1252516 · Cited by 42
“” A downstream kinase cascade, involving serial phosphorylation of downstream kinases, such as RAF, ERK and MEK, ultimately triggers transcription factor activation, leading to increased cellular proliferation, migration and survival (1 – 3).”
BackgroundFrequent HRAS Mutations in Malignant Ectomesenchymoma
Huang, S., Alaggio, R., Sung, Y., Chen, C., Zhang, L., Kao, Y., Agaram, N. P., Wexler, L. H., & Antonescu, C. R. (2016) · The American Journal of Surgical Pathology · doi:10.1097/pas.0000000000000612 · Cited by 36
Zhang, J., Chang, L., Jin, H., Xia, Y., Wang, L., He, W., Li, W., & Chen, H. (2016) · Experimental Biology and Medicine · doi:10.1177/1535370216644530 · Cited by 35
“The carcinogenesis for lung cancer by tobacco smoke derived significant attentions on B[a]P and NNK in lung cancer development and progression, inducing the mutations of Ras genes or P53 via different signal pathways.(12,13) For example, NNK-induced Kras mutation from GGT to GAT at site 12 in human lung cancer tissue,…”
BackgroundTherapeutic potential of combined BRAF/MEK blockade in BRAF-wild type preclinical tumor models
Curatolo, A. D., Conciatori, F., Incani, U. C., Bazzichetto, C., Falcone, I., Corbo, V., D’Agosto, S. L., Eramo, A., Sette, G., Sperduti, I., et al. (2018) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-018-0820-5 · Cited by 36
Han, S., Li, X., Xia, Y., Yu, Z., Cai, N., Malwal, S. R., Han, X., Oldfield, E., & Zhang, Y. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01405 · Cited by 36
Drug resistance in targeted cancer therapies with RAF inhibitors
Degirmenci, U., Yap, J., Sim, Y. R. M., Qin, S., & Hu, J. (2021) · Cancer Drug Resistance · doi:10.20517/cdr.2021.36 · Cited by 36
Díaz, E. C. G., Lee, A. G., Sayles, L. C., Feria, C., Sweet-Cordero, A., & Yang, F. (2022) · Advanced Healthcare Materials · doi:10.1002/adhm.202200768 · Cited by 35
RETRACTED: Recent advances in glioblastoma multiforme therapy: A focus on autophagy regulation
Sanati, M., Binabaj, M. M., Ahmadi, S. S., Aminyavari, S., Javid, H., Mollazadeh, H., Bibak, B., Mohtashami, E., Jamialahmadi, T., Afshari, A. R., et al. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.113740 · Cited by 35
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Integrating genomics in head and neck cancer treatment: Promises and pitfalls
Thariat, J., Vignot, S., Lapierre, A., Falk, A. T., Guigay, J., Obberghen‐Schilling, E. V., & Milano, G. A. (2015) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2015.03.005 · Cited by 35
“Although ost lung and head and neck carcinomas share exposure o tobacco, their activating mutations differ, underlining the issue-specific nature of malignancies despite exposure to imilar carcinogens [8].”
BackgroundInfluentialAbsolute Quantification of Endogenous Ras Isoform Abundance
Mageean, C. J., Griffiths, J. R., Smith, D. L., Clague, M. J., & Prior, I. A. (2015) · PLoS ONE · doi:10.1371/journal.pone.0142674 · Cited by 36
“These mutations are present in approximately 30% of all tumours screened and oncogenic mutations and/or amplification of members of the Ras pathways are present in almost all cancers [1, 2].”
BackgroundSelf-citationThe Allosteric Switch and Conformational States in Ras GTPase Affected by Small Molecules
Johnson, C. W., & Mattos, C. (2013) · The Enzymes · doi:10.1016/b978-0-12-416749-0.00003-8 · Cited by 35
“Oncogenic Ras is found in about 20% of all cancers, with mutations in the K-Ras isoform being particularly prominent in human tumors [11].”
BackgroundInfluentialSelf-citationMembrane Curvature and Lipid Composition Synergize To Regulate N-Ras Anchor Recruitment
Larsen, J. B., Kennard, C., Pedersen, S. L., Jensen, K. J., Uline, M. J., Hatzakis, N. S., & Stamou, D. G. (2017) · Biophysical Journal · doi:10.1016/j.bpj.2017.06.051 · Cited by 38
Structure, signaling and the drug discovery of the Ras oncogene protein
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“in human cancers, are encoded by three expressed genes: H-, K-, and N-Ras (13).”
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“Next, we depleted PM PtdIns4P and PtdIns(4,5)P2 separately to examine the contribution of these lipids individually to the PM localization of K-Ras.”
BackgroundMethodInfluentialDiscovery of Quinazolines That Activate SOS1-Mediated Nucleotide Exchange on RAS
Abbott, J. R., Patel, P. A., Howes, J. E., Akan, D. T., Kennedy, J. P., Burns, M. C., Browning, C. F., Sun, Q., Rossanese, O. W., Phan, J., et al. (2018) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.8b00296 · Cited by 37
Real-Time In-Cell NMR Reveals the Intracellular Modulation of GTP-Bound Levels of RAS
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“MutationsofRAS,mostfrequentlyatthreehotspotcodons encodingG12,G13,orQ61,causeaberrantactivationofRASpri-marily by impairing hydrolysis of GTP (Lu et al., 2016; Prior et al., 2012).”
BackgroundTRP Channels and Small GTPases Interplay in the Main Hallmarks of Metastatic Cancer
Chinigò, G., Fiorio, A., & Gkika, D. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.581455 · Cited by 34
Epithelial–Myoepithelial Carcinoma
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Recent advances in precision medicine for pancreatic ductal adenocarcinoma
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“This is an important gap given the fact that oncogenic RAS mutations are found over 30% of all human cancers (Prior et al., 2012), and RAS activation is even more common along with highly prevalent and consequential involvement of RAS downstream effector pathways (RAF/MAPK, PI3K/AKT) across the…”
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Self-citation
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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