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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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BackgroundIrradiation induces diverse changes in invasive potential in cancer cell lines
Fujita, M., Yamada, S., & Imai, T. (2015) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2015.09.003 · Cited by 57
Genetic Progression of High Grade Prostatic Intraepithelial Neoplasia to Prostate Cancer
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Evidence for Oncolytic Virotherapy: Where Have We Got to and Where Are We Going?
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“There would, therefore, seem to be a strong rationale for the use of reovirus in tumours with a high incidence of Ras mutations [29].”
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Translational control of ERK signaling through miRNA/4EHP-directed silencing
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“Mutations at codon 61 also show similar variability [17].”
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Hampton, S. E., Dore, T. M., & Schmidt, W. K. (2018) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409238.2018.1431606 · Cited by 53
“Assay type Reporter Sequencea Detection method In vivo GFP-Ras (H, N, K4a, K4b) (∼45 kDa) GFP-H-Ras-CVLS GFP-N-Ras-CVVM GFP-KRas4a-CIIM GFP-K-Ras4b-CVIM Cell-based fluorescence GFP-Ras2p (∼60kDa) GFP-Ras2p-CIIS Cell-based fluorescence a-factor precursor (36-mer) Mature a-factor peptide-CVIA Bioactivity In vitro a-fact…”
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“Indeed, common genetic alterations such as amplification of the MYC oncogenes, (~28% pan-cancer) [15], mutations of the RAS family (~16% of cancers) [22], or alterations of tumor suppressor genes such as TP53 (mutated in 50% of cancers) [23] are difficult to target directly and currently lack FDA approved drugs.”
BackgroundSLIT2/ROBO1-signaling inhibits macropinocytosis by opposing cortical cytoskeletal remodeling
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BackgroundKRAS Switch Mutants D33E and A59G Crystallize in the State 1 Conformation
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ERBB2 and KRAS alterations mediate response to EGFR inhibitors in early stage gallbladder cancer
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The importance of Ras in drug resistance in cancer
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“Regulation of RAS by GTPase activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs) has been well studied (32), as has activation of RAS by mutation (33), but other mechanisms that regulate RAS-driven signaling have received less attention.”
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Lessons from computer simulations of Ras proteins in solution and in membrane
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“In fact, Ras is found mutated in about 15% of all human tumors and in up to 90% of cases in specific tumor types [19], as well as in a number of developmental disorders [20, 21].”
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“For protein expression in Escherichia coli, the pQE-A1 plasmid was generated from pQE-30 Xa (Qiagen, Hilden, Germany) with the following modifications; the sequence coding for the PreScission protease (GE Healthcare) recognition site and a sequence coding for the 12-amino acid A1 tag followed by a BglII restriction si…”
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“The exact molecular and cellular mechanisms that lead to the observed phenotypes are still largely unclear (Prior et al., 2012).”
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“Such mutations are most frequently observed in carcinomas of the pancreas (63-90%), colon (36-50%), and lung (19-30%) [1, 2].”
BackgroundTherapeutic Targeting of mTOR in T-Cell Acute Lymphoblastic Leukemia: An Update
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“N-RAS and K-RAS activating mutations seem to occur more frequently in early T-cell progenitor (ETP)-”
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Annual review of KRAS inhibitors in 2022
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“The altered RASpathwayby mutated RASoverexpression has been frequently observed in colorectal tumors 38 .”
BackgroundExperimental mouse models for translational human cancer research
Zhou, Y., Xia, J., Xu, S., She, T., Zhang, Y., Sun, Y., Wen, M., Jiang, T., Xiong, Y., & Lei, J. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1095388 · Cited by 52
RAB27B controls palmitoylation-dependent NRAS trafficking and signaling in myeloid leukemia
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“RAS pathway mutations, including mutations in RAS, CBL, NF1, and PTPN11 genes, are among the most prevalent mutations in solid and hematological malignancies (10, 11).”
BackgroundTargeting KRAS mutations in pancreatic cancer: opportunities for future strategies
Linehan, A., O’Reilly, M., McDermott, R., & O'Kane, G. M. (2024) · Frontiers in Medicine · doi:10.3389/fmed.2024.1369136 · Cited by 57
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“Since the previously identified RAS aberrations are all activating mutations (at residues G12, G13 or Q61), we wondered whether small molecule inhibitors targeting RAS pathway components could suppress RASmutant leukemic cells [3, 7].”
Distinct genomic profile and specific targeted drug responses in adult cerebellar glioblastoma
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“It is estimated that over 50%of colon cancers are driven bymutations in the RAS gene (3).”
BackgroundMishto, M., Mansurkhodzhaev, A., Ge, Y., Bitra, A., Cordfunke, R. A., Henze, S., Paul, D., Sidney, J., Urlaub, H., Neefjes, J., et al. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02572 · Cited by 48
“In particular, KRAS is frequently mutated in cancers with an average of 22% cancers carrying a KRAS mutation, a frequency that rises to 33–61% in colorectal cancer and pancreatic adenocarcinoma (38).”
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“The three Ras genes (Kras, Nras, and Hras) are among the most mutated genes associated with cancer (mutated in 90% of pancreatic, 35% of lung, and 45% of colon cancers), and, in particular, Kras is the isoform most prevalently mutated in lung cancers (47, 48).”
BackgroundAn Introduction to Fundamentals of Cancer Biology
Sriharikrishnaa, S., Suresh, P. S., & Kabekkodu, S. P. (2023) · Biological and medical physics, biomedical engineering · doi:10.1007/978-3-031-31852-8_11 · Cited by 55
Selective targeting of point-mutated KRAS through artificial microRNAs
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Marín‐Ramos, N. I., Balabasquer, M., Ortega-Nogales, F. J., Torrecillas, I. R., Gil-Ordóñez, A., Marcos‐Ramiro, B., Aguilar-Garrido, P., Cushman, I., Romero, A., Medrano, F. J., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b00145 · Cited by 51
Intrinsically disordered proteins: Ensembles at the limits of Anfinsen's dogma
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Mechanistic model of MAPK signaling reveals how allostery and rewiring contribute to drug resistance
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“Driving oncogenic mutations are found in multiple components in or upstream of the MAPK pathway (Burotto et al, 2014), commonly KRAS (G12C/D/V, G13C/D), NRAS (Q61H/K)(Prior et al, 2012), BRAF (V600E/K) and less commonly MEK and ERK (Gao et al, 2018).”
BackgroundRegulation of K-Ras4B Membrane Binding by Calmodulin
Sperlich, B., Kapoor, S., Waldmann, H., Winter, R., & Weise, K. (2016) · Biophysical Journal · doi:10.1016/j.bpj.2016.05.042 · Cited by 49
MEK inhibitors in oncology: a patent review (2015-Present)
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“Frequently altered RAS codons have been found in various cancers including pancreatic, thyroid, colon, lung, and acute myeloid leukemia [18].”
BackgroundTargeting plasma membrane phosphatidylserine content to inhibit oncogenic KRAS function
Kattan, W. E., Chen, W., Ma, X., Lan, T.-H., van der Hoeven, D., van der Hoeven, R., & Hancock, J. F. (2019) · Life Science Alliance · doi:10.26508/lsa.201900431 · Cited by 46
“The major clinical problem is KRAS, which is mutated in >90% of pancreatic cancers, ~50% of colon cancers, and ~25% of non – small cell lung cancer (Prior et al, 2012).”
Fan, M., Xia, P., Liu, B., Zhang, L., Wang, Y., Gao, X., & Li, L.-H. (2019) · Breast Cancer Research · doi:10.1186/s13058-019-1199-8 · Cited by 30
Why Are Some Driver Mutations Rare?
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Cytotoxicity of juglone and thymoquinone against pancreatic cancer cells
Karki, N., Aggarwal, S., Laine, R. A., Greenway, F. L., & Losso, J. N. (2020) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2020.109142 · Cited by 47
Targeting KRAS in Solid Tumors: Current Challenges and Future Opportunities of Novel KRAS Inhibitors
Indini, A., Rijavec, E., Ghidini, M., Cortellini, A., & Grossi, F. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13050653 · Cited by 49
“Different solid tumors are correlated with mutations in certain isoforms of RAS, with Kirsten RAS (KRAS) being the most frequently mutated isoform [5].”
BackgroundFunctional and biological heterogeneity of KRAS Q61 mutations
Huynh, M. V., Hobbs, G. A., Schaefer, A., Pierobon, M., Carey, L. M., Diehl, J. N., DeLiberty, J. M., Thurman, R. D., Cooke, A. R., Goodwin, C. M., et al. (2022) · Science Signaling · doi:10.1126/scisignal.abn2694 · Cited by 47
“Based largely on the study of HRASG12V, the widely held perception is that these mutant RAS proteins are impaired in GAP-mediated GTP hydrolysis, thereby disrupting the GDP-GTP cycle and populating RAS in the active GTP-bound state (5).”
BackgroundTyrosine phosphorylation of RAS by ABL allosterically enhances effector binding
Ting, P. Y., Johnson, C. W., Fang, C., Cao, X., Graeber, T. G., Mattos, C., & Colicelli, J. (2015) · The FASEB Journal · doi:10.1096/fj.15-271510 · Cited by 45
“pFastBacABL1(1-531)andABL2havebeendescribedpreviously (26).”
BackgroundMethodInfluentialSelf-citationXi, Z., Mu, Y., Li, Y., Xie, C., Holst, J., Liu, T., Cai, S., Lao, Y., Tan, H., Xu, H., et al. (2016) · Cell Death and Disease · doi:10.1038/cddis.2016.123 · Cited by 46
Lau, H. Y., Tang, J., Casey, P. J., & Wang, M. (2017) · Oncogene · doi:10.1038/onc.2016.508 · Cited by 46
Blocking Ras inhibition as an antitumor strategy
Marín‐Ramos, N. I., Ortega‐Gutiérrez, S., & López-Rodríguez, M. L. (2018) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2018.01.017 · Cited by 46
KRAS targeting antibody synergizes anti-cancer activity of gemcitabine against pancreatic cancer
Kang, Y. W., Lee, J. E., Jung, K. H., Son, M. K., Shin, S., Kim, S., Fang, Z., YAN, H. H., Park, J. H., Han, B., et al. (2018) · Cancer Letters · doi:10.1016/j.canlet.2018.09.013 · Cited by 45
RAS genes in colorectal carcinoma: pathogenesis, testing guidelines and treatment implications
Saeed, O. A. M., Antonio Lopez-beltran, B., Fisher, K. W., Scarpelli, M., Montironi, R., Cimadamore, A., Massari, F., Santoni, M., & Liang Cheng, C. (2018) · Journal of Clinical Pathology · doi:10.1136/jclinpath-2018-205471 · Cited by 47
Mutational profile of endometrial hyperplasia and risk of progression to endometrioid adenocarcinoma
Russo, M., Newell, J. M., Budurlean, L., Houser, K. R., Sheldon, K. E., Kesterson, J. P., Phaëton, R., Hossler, C., Rosenberg, J., DeGraff, D. J., et al. (2020) · Cancer · doi:10.1002/cncr.32822 · Cited by 46
“Time to progression, hysterectomy, or last follow-up, median (range), mo 35 (16-259) 109 (9-140)”
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Druggable Orthosteric and Allosteric Hot Spots to Target Protein-protein Interactions
Ma, B., & Nussinov, R. (2014) · Current Pharmaceutical Design · doi:10.2174/13816128113199990073 · Cited by 45
“Forty four point oncogenic mutations have been found in Ras, and more than 99% of them are located at condons 12, 13, and 61 [9].”
BackgroundAssessing optimal: inequalities in codon optimization algorithms
Ranaghan, M. J., Li, J. J., Laprise, D., & Garvie, C. W. (2021) · BMC Biology · doi:10.1186/s12915-021-00968-8 · Cited by 43
“34), it is a therapeutically important target implicated in a wide variety of cancers [48], codon usage has been tied to expression levels in bacteria and mammalian cells [44, 49, 50], and there are several reports publishing their CDS with purified yield (enabling correlation of CDS with recombinant product).”
BackgroundChakraborty, J., Chakraborty, S., Chakraborty, S., & Narayan, M. (2023) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2023.194988 · Cited by 47
Targeting the RAS upstream and downstream signaling pathway for cancer treatment
Hossain, M. A. (2024) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2024.176727 · Cited by 51
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Neoantigens in Hematologic Malignancies
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“Since Kras mutations predominantly occur at codon 12 and occasionally at codons 13 and 61 [19], we then crossed znf322a transgenic mice with KrasG12D lung-specific transgenic mice to generate KrasG12D/znf322a double transgenic mice.”
RAS oncogenic activity predicts response to chemotherapy and outcome in lung adenocarcinoma
East, P., Kelly, G. P., Biswas, D., Marani, M., Hancock, D. C., Creasy, T. H., Sachsenmeier, K. F., Swanton, C., Downward, J., & Trécesson, S. D. C. (2022) · Nature Communications · doi:10.1038/s41467-022-33290-0 · Cited by 42
The role of KRAS splice variants in cancer biology
Nuevo‐Tapioles, C., & Philips, M. R. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.1033348 · Cited by 48
“RAS genes are the most frequently mutated oncogenes in cancer and among the RAS genes, KRAS mutations are most frequently associated with tumors (Prior et al., 2012).”
BackgroundRole of RAS signaling in ovarian cancer
Therachiyil, L., Anand, A., Azmi, A., Bhat, A. A., Korashy, H. M., & Shahab Uddin, M. S. (2022) · F1000Research · doi:10.12688/f1000research.126337.1 · Cited by 46
Injury prevents Ras mutant cell expansion in mosaic skin
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Oncogenic mutations and dysregulated pathways in obesity-associated hepatocellular carcinoma
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Mosaicism in Cutaneous Disorders
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“Indeed, the missense mutations affecting these residues, which lead to a constitutively active GTP-bound Ras, account for the majority of identified mutations in cancer and RASopathies (55, 100).”
InfluentialHowes, J. E., Akan, D. T., Burns, M. C., Rossanese, O. W., Waterson, A. G., & Fesik, S. W. (2018) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-17-0666 · Cited by 42
“We hypothesized this is due to constitutive activation of RAS in RAS-mutant cell lines (28).”
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Status of KRAS in iPSCs Impacts upon Self-Renewal and Differentiation Propensity
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“The mutations at hotspots (G12, G13, and G61) in the RAS genes cause accumulation of the GTP-bound form due to defective intrinsic GTP hydrolysis activity and resistance to GTPase-activating proteins (Prior et al., 2012).”
BackgroundKRAS(G12C)–AMG 510 interaction dynamics revealed by all-atom molecular dynamics simulations
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KRAS/BRAF mutations in brain arteriovenous malformations: A systematic review and meta-analysis
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“This indicates the context-dependent and tissuespecific role of the RAS/RAF pathway in vascular tissue or it might demonstrate that there is a requirement for multiple additional genetic hits in order to develop cancer which is opposed to a monogenetic nature of arteriovenous malformations.(16,34)The results of freque…”
BackgroundAdvances and perspectives of proteolysis targeting chimeras (PROTACs) in drug discovery
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“Median age, years (range) 62 (24-81) 62 (43-80) 62 (24-81) .”
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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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