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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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Multivalent Small-Molecule Pan-RAS Inhibitors
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“However, widely expressed (93% PDAC and 50% CRC) KRAS driver mutations (mKRASs) are attractive immunotherapy targets required for tumor survival with uniform expression throughout disease progression 9,10 .”
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“bound KRAS and persistent activation of downstream signals.(3) KRAS mutations are present in approximately 15-30% of patients with NSCLC, respectively.”
BackgroundA Comparative Analysis of Individual RAS Mutations in Cancer Biology
Muñoz-Maldonado, C., Zimmer, Y., & Medová, M. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.01088 · Cited by 254
“The mutations rates at each codon differ between the RAS proteins (2).”
BackgroundInfluentialHunter, J. C., Gurbani, D., Ficarro, S. B., Carrasco, M. A., Lim, S. M., Choi, H. G., Xie, T., Marto, J. A., Chen, Z., Gray, N. S., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1404639111 · Cited by 242
“Approximately 30% of all human cancers contain activating Ras mutations, making them one of the most common identifiable molecular drivers of cancer (1, 2).”
BackgroundYi, M., Nissley, D. V., McCormick, F. P., & Stephens, R. M. (2020) · Scientific Reports · doi:10.1038/s41598-020-66986-8 · Cited by 235
Metabolic networks in mutant KRAS-driven tumours: tissue specificities and the microenvironment
Kerk, S. A., Papagiannakopoulos, T. Y., Shah, Y. M., & Lyssiotis, C. A. (2021) · Nature reviews. Cancer · doi:10.1038/s41568-021-00375-9 · Cited by 246
Bond, M. J., & Crews, C. M. (2021) · RSC Chemical Biology · doi:10.1039/d1cb00011j · Cited by 232
Allosteric Effects of the Oncogenic RasQ61L Mutant on Raf-RBD
Fetics, S., Guterres, H., Kearney, B. M., Buhrman, G., Ma, B., Nussinov, R., & Mattos, C. (2015) · Structure · doi:10.1016/j.str.2014.12.017 · Cited by 225
“It has become increasingly apparent that Ras oncogenic mutants occur at very different rates in different cancers and that they affect distinct pathways in the cell (Prior et al., 2012).”
Self-citationComprehensive assessment of cancer missense mutation clustering in protein structures
Kamburov, A., Lawrence, M. S., Polak, P. P., Leshchiner, I., Lage, K., Golub, T. R., Lander, E. S., & Getz, G. A. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1516373112 · Cited by 222
“1), disturb the GTPase activity of the oncoprotein, locking it in its active, GTP-bound state (68).”
BackgroundK-Ras4A splice variant is widely expressed in cancer and uses a hybrid membrane-targeting motif
Tsai, F. D., Lopes, M. S., Zhou, M., Court, H., Ponce, O., Fiordalisi, J. J., Gierut, J. J., Cox, A. D., Haigis, K. M., & Philips, M. R. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1412811112 · Cited by 238
“R genes are the most frequently mutated oncogenes in human cancer (1) and therefore, considered among the most important targets for anticancer therapy.”
BackgroundRas nanoclusters: Versatile lipid-based signaling platforms
Zhou, Y., & Hancock, J. F. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2014.09.008 · Cited by 224
“This control is subverted in ~15% of all human tumors which express Ras proteins with oncogenic mutations that prevent GAP action and lock Ras in the GTP-bound state [3,4].”
BackgroundERK5: Structure, regulation and function
Nithianandarajah-Jones, G. N., Wilm, B., Goldring, C. E., Müller, J., & Cross, M. J. (2012) · Cellular Signalling · doi:10.1016/j.cellsig.2012.07.007 · Cited by 226
The Structural Basis of Oncogenic Mutations G12, G13 and Q61 in Small GTPase K-Ras4B
Lu, S., Jang, H., Nussinov, R., & Zhang, J. (2016) · Scientific Reports · doi:10.1038/srep21949 · Cited by 219
Young, A., Lou, D., & McCormick, F. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0231 · Cited by 211
“Oncogenic RAS alleles differ from their wild-type counterpart by a single missense point mutation that results in an amino acid substitution typically at position 12, 13, or 61 (6, 7).”
Aging and the rise of somatic cancer-associated mutations in normal tissues
Risques, R. A., & Kennedy, S. R. (2018) · PLoS Genetics · doi:10.1371/journal.pgen.1007108 · Cited by 219
Small-molecule modulation of Ras signaling
Spiegel, J., Cromm, P. M., Zimmermann, G., Grossmann, T. N., & Waldmann, H. (2014) · Nature Chemical Biology · doi:10.1038/nchembio.1560 · Cited by 220
Ras and Rap1: A tale of two GTPases
Shah, S. K., Brock, E. J., Ji, K., & Mattingly, R. R. (2018) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2018.03.005 · Cited by 217
“G12 mutations comprise 83% of all K-Ras mutations, while G13 mutations make up 14% of the profile, and Q61 mutations are less frequent (2%).”
BackgroundInfluentialHuang, J., Jiang, G., Song, Q., Gu, X. Q., Meng, H., Wang, X.-L., Song, H., Chen, L., Lin, Y., Jiang, D. M., et al. (2017) · Nature Communications · doi:10.1038/ncomms15144 · Cited by 212
“Three Ras family members including KRas , HRas and NRas are expressed in all mammalian cells, and promote oncogenesis when mutation occurs, which produce the functional redundancy of GTPase and downstream cascades such as the macropinocytosis pathway 7 .”
Cancer, metastasis, and the epigenome
Kiri, S., & Ryba, T. (2024) · Molecular Cancer · doi:10.1186/s12943-024-02069-w · Cited by 228
“Ras frequently suffers mutational insult in cancers, with mutation hotspots at residues 12, 13, and 61 [46].”
BackgroundGTP-Dependent K-Ras Dimerization
Muratcioglu, S., Chavan, T. S., Freed, B. C., Jang, H., Khavrutskii, L., Freed, R. N., Dyba, M. A., Stefanisko, K., Tarasov, S. G., Gursoy, A., et al. (2015) · Structure · doi:10.1016/j.str.2015.04.019 · Cited by 202
“K-Ras, which is frequently mutated in human cancer (Lawrence et al., 2014), is the most potent activator of Raf among Ras isoforms (Prior et al., 2012).”
BackgroundKRAS inhibitors: resistance drivers and combinatorial strategies
Isermann, T., Sers, C., Der, C. J., & Papke, B. (2024) · Trends in cancer · doi:10.1016/j.trecan.2024.11.009 · Cited by 217
K-Ras promotes tumorigenicity through suppression of non-canonical Wnt signaling
Wang, M.-T., Holderfield, M., Galeas, J., Delrosario, R., To, M. D., Balmain, A., & McCormick, F. (2015) · Cell · doi:10.1016/j.cell.2015.10.041 · Cited by 196
“K-Ras mutations occur at high frequency in pancreatic and colorectal cancers and in lung adenocarcinomas, while N-Ras and H-Ras mutations are far less common (Prior et al., 2012).”
BackgroundDrugging Ras GTPase: a comprehensive mechanistic and signaling structural view
Lu, S., Jang, H., Gu, S., Zhang, J., & Nussinov, R. (2016) · Chemical Society Reviews · doi:10.1039/c5cs00911a · Cited by 188
Correlation of mutation profile and response in patients with myelofibrosis treated with ruxolitinib
Patel, K. P., Newberry, K. J., Luthra, R., Jabbour, E. J., Pierce, S. A., Cortes, J. E., Singh, R. R., Mehrotra, M., Routbort, M. J., Luthra, M. G., et al. (2015) · Blood · doi:10.1182/blood-2015-03-633404 · Cited by 195
“Overall survival, mean (weeks) 207 (7-387) 194 (43-372) 243 (7-387) 246 (60-336) .”
InfluentialApproach for targeting Ras with small molecules that activate SOS-mediated nucleotide exchange
Burns, M. C., Sun, Q., Daniels, R. N., Camper, D., Kennedy, J. P., Phan, J., Olejniczak, E. T., Lee, T., Waterson, A. G., Rossanese, O. W., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1315798111 · Cited by 199
“Indeed, aberrant Ras signaling plays a role in up to 30% of all human cancers, with the highest incidence of Ras mutations occurring in carcinomas of the pancreas (63–90%), colon (36–50%), and lung (19–30%) (2, 3).”
BackgroundThe path to the clinic: a comprehensive review on direct KRASG12C inhibitors
Kwan, A. K., Piazza, G. A., Keeton, A. B., & Leite, C. A. (2022) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-021-02225-w · Cited by 200
“Among mutations in the three RAS genes, gain-of-function missense mutations in KRAS account for the majority of RAS gene mutations (75%), followed by NRAS mutations (17%) and HRAS mutations (7%) [43, 45].”
BackgroundKRAS-related proteins in pancreatic cancer
Mann, K. M., Ying, H., Juan, J. M., Jenkins, N. A., & Copeland, N. G. (2016) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2016.09.003 · Cited by 192
“While G12D or G12V mutations are the most common KRAS activating mutations found in human PDAC, additional rare mutations in codon G13 and Q61 have also been found (Jones et al., 2008; Biankin et al., 2012; Prior et al., 2012; Witkiewicz et al., 2015).”
BackgroundKRAS G12C Game of Thrones, which direct KRAS inhibitor will claim the iron throne?
Nagasaka, M., Li, Y., Sukari, A., Ou, S.-H. I., Al-Hallak, M. N., & Azmi, A. S. (2020) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2020.101974 · Cited by 185
“KRAS is a GTP-binding protein that links receptor tyrosine kinase activation to intracellular signaling [5, 6].”
BackgroundRAS: Striking at the Core of the Oncogenic Circuitry
Gimple, R. C., & Wang, X. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.00965 · Cited by 174
Wang, Z., Liu, F., Fan, N., Zhou, C., Li, D., MacVicar, T., Dong, Q., Bruns, C. J., & Zhao, Y. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.589508 · Cited by 189
“RAS proteins are frequently mutated in many types of human cancers (54).”
BackgroundRAS-mediated oncogenic signaling pathways in human malignancies
Khan, A. Q., Kuttikrishnan, S., Siveen, K. S., Prabhu, K. S., Shanmugakonar, M., Al‐Naemi, H. A., Haris, M., Dermime, S., & Shahab Uddin, M. S. (2018) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2018.03.001 · Cited by 185
The current understanding on the impact of KRAS on colorectal cancer
Meng, M., Zhong, K., Jiang, T., Liu, Z., Kwan, H. Y., & Su, T. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.111717 · Cited by 171
E3 ligases and deubiquitinating enzymes regulating the MAPK signaling pathway in cancers
Park, H., & Baek, K. (2022) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2022.188736 · Cited by 184
KRAS Mutant Pancreatic Cancer: No Lone Path to an Effective Treatment
Zeitouni, D., Pylayeva‐Gupta, Y., Der, C. J., & Bryant, K. L. (2016) · Cancers · doi:10.3390/cancers8040045 · Cited by 191
“The three RAS genes constitute the most frequently mutated oncogene family in human cancers [14,18]; however, the specific isoform and amino acid mutation varies among cancers.”
BackgroundArginase 1 is a key driver of immune suppression in pancreatic cancer
Menjivar, R. E., Nwosu, Z. C., Du, W., Donahue, K. L., Hong, H. S., Espinoza, C. E., Brown, K. L., Velez-Delgado, A., Yan, W., Lima, F., et al. (2023) · eLife · doi:10.7554/elife.80721 · Cited by 189
“, 2020), a common mutation in nonsmall cell lung cancer (Prior et al., 2012); initial clinical data show not only dramatic responses but also cases of primary or secondary resistance (Awad et al.”
BackgroundStructural basis of recognition of farnesylated and methylated KRAS4b by PDEδ
Dharmaiah, S., Bindu, L. K., Tran, T. H., Gillette, W., Frank, P. H., Ghirlando, R., Nissley, D. V., Esposito, D., McCormick, F. P., Stephen, A. G., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1615316113 · Cited by 177
Biomarkers That Currently Affect Clinical Practice in Lung Cancer: EGFR, ALK, MET, ROS-1, and KRAS
Korpanty, G. J., Graham, D. M., Vincent, M. D., & Leighl, N. B. (2014) · Frontiers in Oncology · doi:10.3389/fonc.2014.00204 · Cited by 179
“Most KRAS mutations in NSCLC are single amino acid substitutions in codon 12 (80%) and to a lesser extent in codons 13 and 61 (30).”
BackgroundFluorine-containing drugs approved by the FDA in 2021
He, J., Li, Z., Dhawan, G., Zhang, W., Sorochinsky, A. E., Butler, G., Soloshonok, V. A., & Han, J. (2022) · Chinese Chemical Letters · doi:10.1016/j.cclet.2022.06.001 · Cited by 175
Overcoming Challenges for CD3-Bispecific Antibody Therapy in Solid Tumors
Middelburg, J., Kemper, K., Engelberts, P. J., Labrijn, A. F., Schuurman, J., & van Hall, T. (2021) · Cancers · doi:10.3390/cancers13020287 · Cited by 178
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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