Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

OPINION

A model for RAS mutation patterns in cancers: finding the sweet spot

Nature Reviews Cancer volume 18, pages 767–777 (2018)Cite this article

Subjects

Abstract

The three RAS genes — HRAS, NRAS and KRAS — are collectively mutated in one-third of human cancers, where they act as prototypic oncogenes. Interestingly, there are rather distinct patterns to RAS mutations; the isoform mutated as well as the position and type of substitution vary between different cancers. As RAS genes are among the earliest, if not the first, genes mutated in a variety of cancers, understanding how these mutation patterns arise could inform on not only how cancer begins but also the factors influencing this event, which has implications for cancer prevention. To this end, we suggest that there is a narrow window or ‘sweet spot’ by which oncogenic RAS signalling can promote tumour initiation in normal cells. As a consequence, RAS mutation patterns in each normal cell are a product of the specific RAS isoform mutated, as well as the position of the mutation and type of substitution to achieve an ideal level of signalling.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Overview of RAS isoforms and signalling.
Fig. 2: The frequency and type of oncogenic mutations in the three RAS genes in human cancers.
Fig. 3: The ‘sweet spot’ model of RAS mutation patterns.
Fig. 4: Factors shaping the bias of RAS mutations in cancer.

Similar content being viewed by others

References

  1. Hancock, J. F. Ras proteins: different signals from different locations. Nat. Rev. Mol. Cell Biol. 4, 373–384 (2003).

    Article  CAS  PubMed  Google Scholar 

  2. Ahearn, I. M., Haigis, K., Bar-Sagi, D. & Philips, M. R. Regulating the regulator: post-translational modification of RAS. Nat. Rev. Mol. Cell Biol. 13, 39–51 (2011).

    Article  CAS  PubMed  Google Scholar 

  3. Bos, J. L., Rehmann, H. & Wittinghofer, A. GEFs and GAPs: critical elements in the control of small G proteins. Cell 129, 865–877 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Simanshu, D. K., Nissley, D. V. & McCormick, F. RAS proteins and their regulators in human disease. Cell 170, 17–33 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Prior, I. A., Lewis, P. D. & Mattos, C. A comprehensive survey of Ras mutations in cancer. Cancer Res. 72, 2457–2467 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Smith, M. J., Neel, B. G. & Ikura, M. NMR-based functional profiling of RASopathies and oncogenic RAS mutations. Proc. Natl Acad. Sci. USA 110, 4574–4579 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Pylayeva-Gupta, Y., Grabocka, E. & Bar-Sagi, D. RAS oncogenes: weaving a tumorigenic web. Nat. Rev. Cancer 11, 761–774 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Ostrem, J. M. & Shokat, K. M. Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design. Nat. Rev. Drug Discov. 15, 771–785 (2016).

    Article  CAS  PubMed  Google Scholar 

  9. Cox, A. D., Fesik, S. W., Kimmelman, A. C., Luo, J. & Der, C. J. Drugging the undruggable RAS: mission possible? Nat. Rev. Drug Discov. 13, 828–851 (2014).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Sukumar, S., Notario, V., Martin-Zanca, D. & Barbacid, M. Induction of mammary carcinomas in rats by nitroso-methylurea involves malignant activation of H-ras-1 locus by single point mutations. Nature 306, 658–661 (1983).

    Article  CAS  PubMed  Google Scholar 

  11. Balmain, A. & Pragnell, I. B. Mouse skin carcinomas induced in vivo by chemical carcinogens have a transforming Harvey-ras oncogene. Nature 303, 72–74 (1983).

    Article  CAS  PubMed  Google Scholar 

  12. Quintanilla, M., Brown, K., Ramsden, M. & Balmain, A. Carcinogen-specific mutation and amplification of Ha-ras during mouse skin carcinogenesis. Nature 322, 78–80 (1986).

    Article  CAS  PubMed  Google Scholar 

  13. Kanda, M. et al. Presence of somatic mutations in most early-stage pancreatic intraepithelial neoplasia. Gastroenterology 142, 730–733.e9 (2012).

    Article  CAS  PubMed  Google Scholar 

  14. Lohr, M., Kloppel, G., Maisonneuve, P., Lowenfels, A. B. & Luttges, J. Frequency of K-ras mutations in pancreatic intraductal neoplasias associated with pancreatic ductal adenocarcinoma and chronic pancreatitis: a meta-analysis. Neoplasia 7, 17–23 (2005).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  15. Hong, S. M. et al. Genome-wide somatic copy number alterations in low-grade PanINs and IPMNs from individuals with a family history of pancreatic cancer. Clin. Cancer Res. 18, 4303–4312 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Wistuba, I. I. & Gazdar, A. F. Lung cancer preneoplasia. Annu. Rev. Pathol. 1, 331–348 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Miller, A. J. & Mihm, M. C. Jr. Melanoma. N. Engl. J. Med. 355, 51–65 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Roh, M. R., Eliades, P., Gupta, S. & Tsao, H. Genetics of melanocytic nevi. Pigment Cell Melanoma Res. 28, 661–672 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Yachida, S. et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 467, 1114–1117 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Zhang, J. et al. Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing. Science 346, 256–259 (2014).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. International Agency for Research on Cancer. Ethyl carbamate. IARC Monographs https://monographs.iarc.fr/wp-content/uploads/2018/06/mono96-12.pdf (2010).

  22. Westcott, P. M. et al. The mutational landscapes of genetic and chemical models of Kras-driven lung cancer. Nature 517, 489–492 (2015).

    Article  CAS  PubMed  Google Scholar 

  23. Johnson, L. et al. Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature 410, 1111–1116 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Guerra, C. et al. Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell 11, 291–302 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Hingorani, S. R. et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7, 469–483 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Braun, B. S. et al. Somatic activation of oncogenic Kras in hematopoietic cells initiates a rapidly fatal myeloproliferative disorder. Proc. Natl Acad. Sci. USA 101, 597–602 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Chan, I. T. et al. Conditional expression of oncogenic K-ras from its endogenous promoter induces a myeloproliferative disease. J. Clin. Invest. 113, 528–538 (2004).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Zhao, Z. et al. p53 loss promotes acute myeloid leukemia by enabling aberrant self-renewal. Genes Dev. 24, 1389–1402 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Haigis, K. M. et al. Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon. Nat. Genet. 40, 600–608 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Sansom, O. J. et al. Loss of Apc allows phenotypic manifestation of the transforming properties of an endogenous K-ras oncogene in vivo. Proc. Natl Acad. Sci. USA 103, 14122–14127 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Dinulescu, D. M. et al. Role of K-ras and Pten in the development of mouse models of endometriosis and endometrioid ovarian cancer. Nat. Med. 11, 63–70 (2005).

    Article  CAS  PubMed  Google Scholar 

  32. O’Dell, M. R. et al. Kras(G12D) and p53 mutation cause primary intrahepatic cholangiocarcinoma. Cancer Res. 72, 1557–1567 (2012).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  33. Burd, C. E. et al. Mutation-specific RAS oncogenicity explains NRAS codon 61 selection in melanoma. Cancer Discov. 4, 1418–1429 (2014).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Li, Q. et al. Hematopoiesis and leukemogenesis in mice expressing oncogenic NrasG12D from the endogenous locus. Blood 117, 2022–2032 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Zhang, J. et al. p53−/− synergizes with enhanced NrasG12D signaling to transform megakaryocyte-erythroid progenitors in acute myeloid leukemia. Blood 129, 358–370 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Chen, X. et al. Endogenous expression of Hras(G12V) induces developmental defects and neoplasms with copy number imbalances of the oncogene. Proc. Natl Acad. Sci. USA 106, 7979–7984 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Vogelstein, B. et al. Cancer genome landscapes. Science 339, 1546–1558 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Yates, L. R. & Campbell, P. J. Evolution of the cancer genome. Nat. Rev. Genet. 13, 795–806 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Tuveson, D. A. et al. Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell 5, 375–387 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. Jackson, E. L. et al. Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes Dev. 15, 3243–3248 (2001).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Parikh, N., Shuck, R. L., Nguyen, T. A., Herron, A. & Donehower, L. A. Mouse tissues that undergo neoplastic progression after K-Ras activation are distinguished by nuclear translocation of phospho-Erk1/2 and robust tumor suppressor responses. Mol. Cancer Res. 10, 845–855 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Morton, J. P. et al. Mutant p53 drives metastasis and overcomes growth arrest/senescence in pancreatic cancer. Proc. Natl Acad. Sci. USA 107, 246–251 (2010).

    Article  CAS  PubMed  Google Scholar 

  43. Collado, M. et al. Tumour biology: senescence in premalignant tumours. Nature 436, 642 (2005).

    Article  CAS  PubMed  Google Scholar 

  44. Ray, K. C. et al. Epithelial tissues have varying degrees of susceptibility to Kras(G12D)-initiated tumorigenesis in a mouse model. PLOS ONE 6, e16786 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Means, A. L., Xu, Y., Zhao, A., Ray, K. C. & Gu, G. A. CK19(CreERT) knockin mouse line allows for conditional DNA recombination in epithelial cells in multiple endodermal organs. Genesis 46, 318–323 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Guerra, C. et al. Tumor induction by an endogenous K-ras oncogene is highly dependent on cellular context. Cancer Cell 4, 111–120 (2003).

    Article  CAS  PubMed  Google Scholar 

  47. Wang, J. et al. Endogenous oncogenic Nras mutation initiates hematopoietic malignancies in a dose- and cell type-dependent manner. Blood 118, 368–379 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Li, Q. et al. Oncogenic Nras has bimodal effects on stem cells that sustainably increase competitiveness. Nature 504, 143–147 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Bender, R. H., Haigis, K. M. & Gutmann, D. H. Activated k-ras, but not h-ras or N-ras, regulates brain neural stem cell proliferation in a raf/rb-dependent manner. Stem Cells 33, 1998–2010 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Garcia-Rendueles, M. E. et al. NF2 loss promotes oncogenic RAS-induced thyroid cancers via YAP-dependent transactivation of RAS proteins and sensitizes them to MEK inhibition. Cancer Discov. 5, 1178–1193 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Gidekel Friedlander, S. Y. et al. Context-dependent transformation of adult pancreatic cells by oncogenic K-Ras. Cancer Cell 16, 379–389 (2009).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  52. Desai, T. J., Brownfield, D. G. & Krasnow, M. A. Alveolar progenitor and stem cells in lung development, renewal and cancer. Nature 507, 190–194 (2014).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  53. Lapouge, G. et al. Identifying the cellular origin of squamous skin tumors. Proc. Natl Acad. Sci. USA 108, 7431–7436 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. White, A. C. et al. Defining the origins of Ras/p53-mediated squamous cell carcinoma. Proc. Natl Acad. Sci. USA 108, 7425–7430 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Brown, K., Strathdee, D., Bryson, S., Lambie, W. & Balmain, A. The malignant capacity of skin tumours induced by expression of a mutant H-ras transgene depends on the cell type targeted. Curr. Biol. 8, 516–524 (1998).

    Article  CAS  PubMed  Google Scholar 

  56. Lampson, B. L. et al. Rare codons regulate KRas oncogenesis. Curr. Biol. 23, 70–75 (2013).

    Article  CAS  PubMed  Google Scholar 

  57. Quax, T. E., Claassens, N. J., Soll, D. & van der Oost, J. Codon bias as a means to fine-tune gene expression. Mol. Cell 59, 149–161 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. Pershing, N. L. et al. Rare codons capacitate Kras-driven de novo tumorigenesis. J. Clin. Invest. 125, 222–233 (2015).

    Article  PubMed  Google Scholar 

  59. Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D. & Lowe, S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593–602 (1997).

    Article  CAS  PubMed  Google Scholar 

  60. Collado, M. & Serrano, M. Senescence in tumours: evidence from mice and humans. Nat. Rev. Cancer 10, 51–57 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  61. Hingorani, S. R. et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4, 437–450 (2003).

    Article  CAS  PubMed  Google Scholar 

  62. Dwyer-Nield, L. D. et al. Epistatic interactions govern chemically-induced lung tumor susceptibility and Kras mutation site in murine C57BL/6J-ChrA/J chromosome substitution strains. Int. J. Cancer 126, 125–132 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  63. Ghanayem, B. I. Inhibition of urethane-induced carcinogenicity in cyp2e1−/− in comparison to cyp2e1+/+ mice. Toxicol. Sci. 95, 331–339 (2007).

    Article  CAS  PubMed  Google Scholar 

  64. Forkert, P. G. Mechanisms of lung tumorigenesis by ethyl carbamate and vinyl carbamate. Drug Metab. Rev. 42, 355–378 (2010).

    Article  CAS  PubMed  Google Scholar 

  65. Nassar, D., Latil, M., Boeckx, B., Lambrechts, D. & Blanpain, C. Genomic landscape of carcinogen-induced and genetically induced mouse skin squamous cell carcinoma. Nat. Med. 21, 946–954 (2015).

    Article  CAS  PubMed  Google Scholar 

  66. McCreery, M. Q. et al. Evolution of metastasis revealed by mutational landscapes of chemically induced skin cancers. Nat. Med. 21, 1514–1520 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Mass, M. J. et al. Ki-ras oncogene mutations in tumors and DNA adducts formed by benz[j]aceanthrylene and benzo[a]pyrene in the lungs of strain A/J mice. Mol. Carcinog. 8, 186–192 (1993).

    Article  CAS  PubMed  Google Scholar 

  68. Beal, M. A., Gagne, R., Williams, A., Marchetti, F. & Yauk, C. L. Characterizing benzo[a]pyrene-induced lacZ mutation spectrum in transgenic mice using next-generation sequencing. BMC Genomics 16, 812 (2015).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  69. Donnelly, P. J. et al. Activation of K-ras in aflatoxin B1-induced lung tumors from AC3F1 (A/J x C3H/HeJ) mice. Carcinogenesis 17, 1735–1740 (1996).

    Article  CAS  PubMed  Google Scholar 

  70. Wang, Y., Wang, Y., Stoner, G. & You, M. ras mutations in 2-acetylaminofluorene-induced lung and liver tumors from C3H/HeJ and (C3H x A/J)F1 mice. Cancer Res. 53, 1620–1624 (1993).

    CAS  PubMed  Google Scholar 

  71. Sills, R. C., Hong, H. L., Melnick, R. L., Boorman, G. A. & Devereux, T. R. High frequency of codon 61K-ras A-->T transversions in lung and Harderian gland neoplasms of B6C3F1 mice exposed to chloroprene (2-chloro-1,3-butadiene) for 2 years, and comparisons with the structurally related chemicals isoprene and 1,3-butadiene. Carcinogenesis 20, 657–662 (1999).

    Article  CAS  PubMed  Google Scholar 

  72. Devereux, T. R., Anderson, M. W. & Belinsky, S. A. Role of ras protooncogene activation in the formation of spontaneous and nitrosamine-induced lung tumors in the resistant C3H mouse. Carcinogenesis 12, 299–303 (1991).

    Article  CAS  PubMed  Google Scholar 

  73. Feng, Z. et al. Preferential DNA damage and poor repair determine ras gene mutational hotspot in human cancer. J. Natl Cancer Inst. 94, 1527–1536 (2002).

    Article  CAS  PubMed  Google Scholar 

  74. Polak, P. et al. Reduced local mutation density in regulatory DNA of cancer genomes is linked to DNA repair. Nat. Biotechnol. 32, 71–75 (2014).

    Article  CAS  PubMed  Google Scholar 

  75. Adar, S., Hu, J., Lieb, J. D. & Sancar, A. Genome-wide kinetics of DNA excision repair in relation to chromatin state and mutagenesis. Proc. Natl Acad. Sci. USA 113, E2124–E2133 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Supek, F. & Lehner, B. Differential DNA mismatch repair underlies mutation rate variation across the human genome. Nature 521, 81–84 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  77. Sun, L. et al. Preferential protection of genetic fidelity within open chromatin by the mismatch repair machinery. J. Biol. Chem. 291, 17692–17705 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  78. Polak, P. et al. Cell-of-origin chromatin organization shapes the mutational landscape of cancer. Nature 518, 360–364 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  79. Blokzijl, F. et al. Tissue-specific mutation accumulation in human adult stem cells during life. Nature 538, 260–264 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  80. Stolze, B., Reinhart, S., Bulllinger, L., Frohling, S. & Scholl, C. Comparative analysis of KRAS codon 12, 13, 18, 61, and 117 mutations using human MCF10A isogenic cell lines. Sci. Rep. 5, 8535 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  81. Park, J. T. et al. Differential in vivo tumorigenicity of diverse KRAS mutations in vertebrate pancreas: a comprehensive survey. Oncogene 34, 2801–2806 (2015).

    Article  CAS  PubMed  Google Scholar 

  82. Seeburg, P. H., Colby, W. W., Capon, D. J., Goeddel, D. V. & Levinson, A. D. Biological properties of human c-Ha-ras1 genes mutated at codon 12. Nature 312, 71–75 (1984).

    Article  CAS  PubMed  Google Scholar 

  83. Der, C. J., Finkel, T. & Cooper, G. M. Biological and biochemical properties of human rasH genes mutated at codon 61. Cell 44, 167–176 (1986).

    Article  CAS  PubMed  Google Scholar 

  84. To, M. D. et al. Kras regulatory elements and exon 4A determine mutation specificity in lung cancer. Nat. Genet. 40, 1240–1244 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  85. Manenti, G. et al. Cis-acting genomic elements of the Pas1 locus control Kras mutability in lung tumors. Oncogene 27, 5753–5758 (2008).

    Article  CAS  PubMed  Google Scholar 

  86. Clavreul, N. et al. S-Glutathiolation by peroxynitrite of p21ras at cysteine-118 mediates its direct activation and downstream signaling in endothelial cells. FASEB J. 20, 518–520 (2006).

    Article  CAS  PubMed  Google Scholar 

  87. Huang, L., Carney, J., Cardona, D. M. & Counter, C. M. Decreased tumorigenesis in mice with a Kras point mutation at C118. Nat. Commun. 5, 5410 (2014).

    Article  CAS  PubMed  Google Scholar 

  88. Franken, S. M. et al. Three-dimensional structures and properties of a transforming and a nontransforming glycine-12 mutant of p21H-ras. Biochemistry 32, 8411–8420 (1993).

    Article  CAS  PubMed  Google Scholar 

  89. Bollag, G. & McCormick, F. Differential regulation of rasGAP and neurofibromatosis gene product activities. Nature 351, 576–579 (1991).

    Article  CAS  PubMed  Google Scholar 

  90. Scheffzek, K. et al. The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants. Science 277, 333–338 (1997).

    Article  CAS  PubMed  Google Scholar 

  91. Lu, S. et al. Ras conformational ensembles, allostery, and signaling. Chem. Rev. 116, 6607–6665 (2016).

    Article  CAS  PubMed  Google Scholar 

  92. Haigis, K. M. KRAS alleles: the devil is in the detail. Trends Cancer 3, 686–697 (2017).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  93. Hunter, J. C. et al. Biochemical and structural analysis of common cancer-associated KRAS mutations. Mol. Cancer Res. 13, 1325–1335 (2015).

    Article  CAS  PubMed  Google Scholar 

  94. Winters, I. P. et al. Multiplexed in vivo homology-directed repair and tumor barcoding enables parallel quantification of Kras variant oncogenicity. Nat. Commun. 8, 2053 (2017).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  95. Kong, G. et al. The ability of endogenous Nras oncogenes to initiate leukemia is codon-dependent. Leukemia 30, 1935–1938 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  96. Barbacid, M. Ras genes. Annu. Rev. Biochem. 56, 779–827 (1987).

    Article  CAS  PubMed  Google Scholar 

  97. Hancock, J. F., Magee, A. I., Childs, J. E. & Marshall, C. J. All ras proteins are polyisoprenylated but only some are palmitoylated. Cell 57, 1167–1177 (1989).

    Article  CAS  PubMed  Google Scholar 

  98. Choy, E. et al. Endomembrane trafficking of ras: the CAAX motif targets proteins to the ER and Golgi. Cell 98, 69–80 (1999).

    Article  CAS  PubMed  Google Scholar 

  99. Apolloni, A., Prior, I. A., Lindsay, M., Parton, R. G. & Hancock, J. F. H-Ras but not K-ras traffics to the plasma membrane through the exocytic pathway. Mol. Cell. Biol. 20, 2475–2487 (2000).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  100. Chiu, V. K. et al. Ras signalling on the endoplasmic reticulum and the Golgi. Nat. Cell Biol. 4, 343–350 (2002).

    Article  CAS  PubMed  Google Scholar 

  101. Matallanas, D. et al. Distinct utilization of effectors and biological outcomes resulting from site-specific Ras activation: Ras functions in lipid rafts and Golgi complex are dispensable for proliferation and transformation. Mol. Cell. Biol. 26, 100–116 (2006).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  102. Cheng, C. M. et al. Compartmentalized Ras proteins transform NIH 3T3 cells with different efficiencies. Mol. Cell. Biol. 31, 983–997 (2011).

    Article  CAS  PubMed  Google Scholar 

  103. Aran, V. & Prior, I. A. Compartmentalized Ras signaling differentially contributes to phenotypic outputs. Cell. Signal. 25, 1748–1753 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  104. Hernandez-Valladares, M. & Prior, I. A. Comparative proteomic analysis of compartmentalised Ras signalling. Sci. Rep. 5, 17307 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  105. Zheng, Z. Y. et al. Wild-type N-Ras, overexpressed in basal-like breast cancer, promotes tumor formation by inducing IL-8 secretion via JAK2 activation. Cell Rep. 12, 511–524 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  106. Yan, J., Roy, S., Apolloni, A., Lane, A. & Hancock, J. F. Ras isoforms vary in their ability to activate Raf-1 and phosphoinositide 3-kinase. J. Biol. Chem. 273, 24052–24056 (1998).

    Article  CAS  PubMed  Google Scholar 

  107. Walsh, A. B. & Bar-Sagi, D. Differential activation of the Rac pathway by Ha-Ras and K-Ras. J. Biol. Chem. 276, 15609–15615 (2001).

    Article  CAS  PubMed  Google Scholar 

  108. Quinlan, M. P., Quatela, S. E., Philips, M. R. & Settleman, J. Activated Kras, but not Hras or Nras, may initiate tumors of endodermal origin via stem cell expansion. Mol. Cell. Biol. 28, 2659–2674 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  109. Voice, J. K., Klemke, R. L., Le, A. & Jackson, J. H. Four human ras homologs differ in their abilities to activate Raf-1, induce transformation, and stimulate cell motility. J. Biol. Chem. 274, 17164–17170 (1999).

    Article  CAS  PubMed  Google Scholar 

  110. Li, W., Zhu, T. & Guan, K. L. Transformation potential of Ras isoforms correlates with activation of phosphatidylinositol 3-kinase but not ERK. J. Biol. Chem. 279, 37398–37406 (2004).

    Article  CAS  PubMed  Google Scholar 

  111. Choi, J. A. et al. Opposite effects of Ha-Ras and Ki-Ras on radiation-induced apoptosis via differential activation of PI3K/Akt and Rac/p38 mitogen-activated protein kinase signaling pathways. Oncogene 23, 9–20 (2004).

    Article  CAS  PubMed  Google Scholar 

  112. Ninomiya, Y. et al. K-Ras and H-Ras activation promote distinct consequences on endometrial cell survival. Cancer Res. 64, 2759–2765 (2004).

    Article  CAS  PubMed  Google Scholar 

  113. Zheng, Z. Y. et al. CHMP6 and VPS4A mediate the recycling of Ras to the plasma membrane to promote growth factor signaling. Oncogene 31, 4630–4638 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  114. Villalonga, P. et al. Calmodulin binds to K-Ras, but not to H- or N-Ras, and modulates its downstream signaling. Mol. Cell. Biol. 21, 7345–7354 (2001).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  115. Abraham, S. J., Nolet, R. P., Calvert, R. J., Anderson, L. M. & Gaponenko, V. The hypervariable region of K-Ras4B is responsible for its specific interactions with calmodulin. Biochemistry 48, 7575–7583 (2009).

    Article  CAS  PubMed  Google Scholar 

  116. Wang, M. T. et al. K-Ras promotes tumorigenicity through suppression of non-canonical Wnt signaling. Cell 163, 1237–1251 (2015).

    Article  CAS  PubMed  Google Scholar 

  117. Alvarez-Moya, B., Lopez-Alcala, C., Drosten, M., Bachs, O. & Agell, N. K-Ras4B phosphorylation at Ser181 is inhibited by calmodulin and modulates K-Ras activity and function. Oncogene 29, 5911–5922 (2010).

    Article  CAS  PubMed  Google Scholar 

  118. Zhang, X., Cao, J., Miller, S. P., Jing, H. & Lin, H. Comparative nucleotide-dependent interactome analysis reveals shared and differential properties of KRas4a and KRas4b. ACS Cent. Sci. 4, 71–80 (2018).

    Article  CAS  PubMed  Google Scholar 

  119. Elad-Sfadia, G., Haklai, R., Balan, E. & Kloog, Y. Galectin-3 augments K-Ras activation and triggers a Ras signal that attenuates ERK but not phosphoinositide 3-kinase activity. J. Biol. Chem. 279, 34922–34930 (2004).

    Article  CAS  PubMed  Google Scholar 

  120. Paz, A., Haklai, R., Elad-Sfadia, G., Ballan, E. & Kloog, Y. Galectin-1 binds oncogenic H-Ras to mediate Ras membrane anchorage and cell transformation. Oncogene 20, 7486–7493 (2001).

    Article  CAS  PubMed  Google Scholar 

  121. Xu, L., Lubkov, V., Taylor, L. J. & Bar-Sagi, D. Feedback regulation of Ras signaling by Rabex-5-mediated ubiquitination. Curr. Biol. 20, 1372–1377 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  122. Adhikari, H. & Counter, C. M. Interrogating the protein interactomes of RAS isoforms identifies PIP5K1A as a KRAS-specific vulnerability. Nat. Commun. 9, 3646 (2018).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  123. Koera, K. et al. K-Ras is essential for the development of the mouse embryo. Oncogene 15, 1151–1159 (1997).

    Article  CAS  PubMed  Google Scholar 

  124. Johnson, L. et al. K-Ras is an essential gene in the mouse with partial functional overlap with N-ras. Genes Dev. 11, 2468–2481 (1997).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  125. Esteban, L. M. et al. Targeted genomic disruption of H-ras and N-ras, individually or in combination, reveals the dispensability of both loci for mouse growth and development. Mol. Cell. Biol. 21, 1444–1452 (2001).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  126. Plowman, S. J. et al. While K-ras is essential for mouse development, expression of the K-ras 4 A splice variant is dispensable. Mol. Cell. Biol. 23, 9245–9250 (2003).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  127. Nakamura, K. et al. Partial functional overlap of the three ras genes in mouse embryonic development. Oncogene 27, 2961–2968 (2008).

    Article  CAS  PubMed  Google Scholar 

  128. Potenza, N. et al. Replacement of K-Ras with H-Ras supports normal embryonic development despite inducing cardiovascular pathology in adult mice. EMBO Rep. 6, 432–437 (2005).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  129. Drosten, M. et al. H-Ras and K-Ras oncoproteins induce different tumor spectra when driven by the same regulatory sequences. Cancer Res. 77, 707–718 (2017).

    Article  CAS  PubMed  Google Scholar 

  130. Sasine, J. P. et al. Wild-type Kras expands and exhausts hematopoietic stem cells. JCI Insight 3, e98197 (2018).

    Article  PubMed Central  Google Scholar 

  131. Parikh, C., Subrahmanyam, R. & Ren, R. Oncogenic NRAS, KRAS, and HRAS exhibit different leukemogenic potentials in mice. Cancer Res. 67, 7139–7146 (2007).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  132. Soh, J. et al. Oncogene mutations, copy number gains and mutant allele specific imbalance (MASI) frequently occur together in tumor cells. PLOS ONE 4, e7464 (2009).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  133. Zhang, Z. et al. Wildtype Kras2 can inhibit lung carcinogenesis in mice. Nat. Genet. 29, 25–33 (2001).

    Article  CAS  PubMed  Google Scholar 

  134. To, M. D., Rosario, R. D., Westcott, P. M., Banta, K. L. & Balmain, A. Interactions between wild-type and mutant Ras genes in lung and skin carcinogenesis. Oncogene 32, 4028–4033 (2013).

    Article  CAS  PubMed  Google Scholar 

  135. Bremner, R. & Balmain, A. Genetic changes in skin tumor progression: correlation between presence of a mutant ras gene and loss of heterozygosity on mouse chromosome 7. Cell 61, 407–417 (1990).

    Article  CAS  PubMed  Google Scholar 

  136. Nan, X. et al. Ras-GTP dimers activate the mitogen-activated protein kinase (MAPK) pathway. Proc. Natl Acad. Sci. USA 112, 7996–8001 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Plowman, S. J., Muncke, C., Parton, R. G. & Hancock, J. F. H-Ras, K-ras, and inner plasma membrane raft proteins operate in nanoclusters with differential dependence on the actin cytoskeleton. Proc. Natl Acad. Sci. USA 102, 15500–15505 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Sarkar-Banerjee, S. et al. Spatiotemporal analysis of K-Ras plasma membrane interactions reveals multiple high order homo-oligomeric complexes. J. Am. Chem. Soc. 139, 13466–13475 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  139. Prakash, P. et al. Computational and biochemical characterization of two partially overlapping interfaces and multiple weak-affinity K-Ras dimers. Sci. Rep. 7, 40109 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  140. Ambrogio, C. et al. KRAS dimerization impacts MEK inhibitor sensitivity and oncogenic activity of mutant KRAS. Cell 172, 857–868.e15 (2018).

    Article  CAS  PubMed  Google Scholar 

  141. Tian, T. et al. Plasma membrane nanoswitches generate high-fidelity Ras signal transduction. Nat. Cell Biol. 9, 905–914 (2007).

    Article  CAS  PubMed  Google Scholar 

  142. Weyandt, J. D., Carney, J. M., Pavlisko, E. N., Xu, M. & Counter, C. M. Isoform-specific effects of wild-type Ras genes on carcinogen-induced lung tumorigenesis in mice. PLOS ONE 11, e0167205 (2016).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  143. Bennecke, M. et al. Ink4a/Arf and oncogene-induced senescence prevent tumor progression during alternative colorectal tumorigenesis. Cancer Cell 18, 135–146 (2010).

    Article  CAS  PubMed  Google Scholar 

  144. Sarkisian, C. J. et al. Dose-dependent oncogene-induced senescence in vivo and its evasion during mammary tumorigenesis. Nat. Cell Biol. 9, 493–505 (2007).

    Article  CAS  PubMed  Google Scholar 

  145. Wright, C. J. & McCormack, P. L. Trametinib: first global approval. Drugs 73, 1245–1254 (2013).

    Article  PubMed  Google Scholar 

  146. Nieto, P. et al. A Braf kinase-inactive mutant induces lung adenocarcinoma. Nature 548, 239–243 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  147. Cisowski, J., Sayin, V. I., Liu, M., Karlsson, C. & Bergo, M. O. Oncogene-induced senescence underlies the mutual exclusive nature of oncogenic KRAS and BRAF. Oncogene 35, 1328–1333 (2016).

    Article  CAS  PubMed  Google Scholar 

  148. Shojaee, S. et al. Erk negative feedback control enables pre-B cell transformation and represents a therapeutic target in acute lymphoblastic leukemia. Cancer Cell 28, 114–128 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  149. Xu, X. et al. Evidence for type II cells as cells of origin of K-Ras-induced distal lung adenocarcinoma. Proc. Natl Acad. Sci. USA 109, 4910–4915 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Liu, J. et al. Non-parallel recombination limits Cre-LoxP-based reporters as precise indicators of conditional genetic manipulation. Genesis 51, 436–442 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  151. Cicchini, M. et al. Context-dependent effects of amplified MAPK signaling during lung adenocarcinoma initiation and progression. Cell Rep. 18, 1958–1969 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  152. Mo, L. et al. Hyperactivation of Ha-ras oncogene, but not Ink4a/Arf deficiency, triggers bladder tumorigenesis. J. Clin. Invest. 117, 314–325 (2007).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  153. Fiorucci, G. & Hall, A. All three human ras genes are expressed in a wide range of tissues. Biochim. Biophys. Acta 950, 81–83 (1988).

    Article  CAS  PubMed  Google Scholar 

  154. The GTEx Consortium. The Genotype-Tissue Expression (GTEx) project. Nat. Genet. 45, 580–585 (2013).

    Article  PubMed Central  CAS  Google Scholar 

  155. Newlaczyl, A. U., Coulson, J. M. & Prior, I. A. Quantification of spatiotemporal patterns of Ras isoform expression during development. Sci. Rep. 7, 41297 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  156. Haseman, J. K., Hailey, J. R. & Morris, R. W. Spontaneous neoplasm incidences in Fischer 344 rats and B6C3F1 mice in two-year carcinogenicity studies: a national toxicology program update. Toxicol. Pathol. 26, 428–441 (1998).

    Article  CAS  PubMed  Google Scholar 

  157. Haines, D. C., Chattopadhyay, S. & Ward, J. M. Pathology of aging B6;129 mice. Toxicol. Pathol. 29, 653–661 (2001).

    Article  CAS  PubMed  Google Scholar 

  158. Mahler, J. F., Stokes, W., Mann, P. C., Takaoka, M. & Maronpot, R. R. Spontaneous lesions in aging FVB/N mice. Toxicol. Pathol. 24, 710–716 (1996).

    Article  CAS  PubMed  Google Scholar 

  159. Candrian, U. et al. Activation of protooncogenes in spontaneously occurring non-liver tumors from C57BL/6 x C3H F1 mice. Cancer Res. 51, 1148–1153 (1991).

    CAS  PubMed  Google Scholar 

  160. Manam, S. et al. Activation of the Ki-ras gene in spontaneous and chemically induced lung tumors in CD-1 mice. Mol. Carcinog. 6, 68–75 (1992).

    Article  CAS  PubMed  Google Scholar 

  161. Manam, S. et al. Activation of the Ha-, Ki-, and N-ras genes in chemically induced liver tumors from CD-1 mice. Cancer Res. 52, 3347–3352 (1992).

    CAS  PubMed  Google Scholar 

  162. Buchmann, A. et al. Mutational activation of the c-Ha-ras gene in liver tumors of different rodent strains: correlation with susceptibility to hepatocarcinogenesis. Proc. Natl Acad. Sci. USA 88, 911–915 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Fox, T. R. et al. Mutational analysis of the H-ras oncogene in spontaneous C57BL/6 x C3H/He mouse liver tumors and tumors induced with genotoxic and nongenotoxic hepatocarcinogens. Cancer Res. 50, 4014–4019 (1990).

    CAS  PubMed  Google Scholar 

  164. Schuhmacher, A. J. et al. A mouse model for Costello syndrome reveals an Ang II-mediated hypertensive condition. J. Clin. Invest. 118, 2169–2179 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  165. Gariboldi, M. et al. A major susceptibility locus to murine lung carcinogenesis maps on chromosome 6. Nat. Genet. 3, 132–136 (1993).

    Article  CAS  PubMed  Google Scholar 

  166. To, M. D. et al. A functional switch from lung cancer resistance to susceptibility at the Pas1 locus in Kras2LA2 mice. Nat. Genet. 38, 926–930 (2006).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  167. Chen, B., You, L., Wang, Y., Stoner, G. D. & You, M. Allele-specific activation and expression of the K-ras gene in hybrid mouse lung tumors induced by chemical carcinogens. Carcinogenesis 15, 2031–2035 (1994).

    Article  CAS  PubMed  Google Scholar 

  168. Matzinger, S. A. et al. Tissue-specific expression of the K-ras allele from the A/J parent in (A/J x TSG-p53) F1 mice. Gene 188, 261–269 (1997).

    Article  CAS  PubMed  Google Scholar 

  169. Dassano, A. et al. Mouse pulmonary adenoma susceptibility 1 locus is an expression QTL modulating Kras-4A. PLOS Genet. 10, e1004307 (2014).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  170. Patek, C. E. et al. Mutationally activated K-ras 4A and 4B both mediate lung carcinogenesis. Exp. Cell Res. 314, 1105–1114 (2008).

    Article  CAS  PubMed  Google Scholar 

  171. Tsai, F. D. et al. K-Ras4A splice variant is widely expressed in cancer and uses a hybrid membrane-targeting motif. Proc. Natl Acad. Sci. USA 112, 779–784 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Ali, M. et al. Codon bias imposes a targetable limitation on KRAS-driven therapeutic resistance. Nat. Commun. 8, 15617 (2017).

    Article  PubMed Central  PubMed  Google Scholar 

  173. Mayr, C. Regulation by 3’-untranslated regions. Annu. Rev. Genet. 51, 171–194 (2017).

    Article  CAS  PubMed  Google Scholar 

  174. Kim, M., Kogan, N. & Slack, F. J. Cis-acting elements in its 3’ UTR mediate post-transcriptional regulation of KRAS. Oncotarget 7, 11770–11784 (2016).

    Article  PubMed Central  PubMed  Google Scholar 

  175. Johnson, S. M. et al. RAS is regulated by the let-7 microRNA family. Cell 120, 635–647 (2005).

    Article  CAS  PubMed  Google Scholar 

  176. Seviour, E. G. et al. Targeting KRas-dependent tumour growth, circulating tumour cells and metastasis in vivo by clinically significant miR-193a-3p. Oncogene 36, 1339–1350 (2017).

    Article  CAS  PubMed  Google Scholar 

  177. Chin, L. J. et al. A SNP in a let-7 microRNA complementary site in the KRAS 3’ untranslated region increases non-small cell lung cancer risk. Cancer Res. 68, 8535–8540 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  178. Mishima, Y. & Tomari, Y. Codon usage and 3’ UTR length determine maternal mRNA stability in zebrafish. Mol. Cell 61, 874–885 (2016).

    Article  CAS  PubMed  Google Scholar 

  179. Jeong, W. J. et al. Ras stabilization through aberrant activation of Wnt/beta-catenin signaling promotes intestinal tumorigenesis. Sci. Signal. 5, ra30 (2012).

    Article  PubMed  Google Scholar 

  180. Kim, S. E. et al. H-Ras is degraded by Wnt/beta-catenin signaling via beta-TrCP-mediated polyubiquitylation. J. Cell Sci. 122, 842–848 (2009).

    Article  CAS  PubMed  Google Scholar 

  181. Mustachio, L. M. et al. Deubiquitinase USP18 loss mislocalizes and destabilizes KRAS in lung cancer. Mol. Cancer Res. 15, 905–914 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  182. Shukla, S. et al. KRAS protein stability is regulated through SMURF2: UBCH5 complex-mediated beta-TrCP1 degradation. Neoplasia 16, 115–128 (2014).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  183. Kang, T. W. et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479, 547–551 (2011).

    Article  CAS  PubMed  Google Scholar 

  184. Lee, K. E. & Bar-Sagi, D. Oncogenic KRas suppresses inflammation-associated senescence of pancreatic ductal cells. Cancer Cell 18, 448–458 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  185. Wellenstein, M. D. & de Visser, K. E. Cancer-cell-intrinsic mechanisms shaping the tumor immune landscape. Immunity 48, 399–416 (2018).

    Article  CAS  PubMed  Google Scholar 

  186. Guerra, C. et al. Pancreatitis-induced inflammation contributes to pancreatic cancer by inhibiting oncogene-induced senescence. Cancer Cell 19, 728–739 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  187. Bailleul, B. et al. Skin hyperkeratosis and papilloma formation in transgenic mice expressing a ras oncogene from a suprabasal keratin promoter. Cell 62, 697–708 (1990).

    Article  CAS  PubMed  Google Scholar 

  188. Stathopoulos, G. T. et al. Epithelial NF-kappaB activation promotes urethane-induced lung carcinogenesis. Proc. Natl Acad. Sci. USA 104, 18514–18519 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Kolodecik, T., Shugrue, C., Ashat, M. & Thrower, E. C. Risk factors for pancreatic cancer: underlying mechanisms and potential targets. Front. Physiol. 4, 415 (2013).

    PubMed  Google Scholar 

  190. Braig, M. et al. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436, 660–665 (2005).

    Article  CAS  PubMed  Google Scholar 

  191. Muzumdar, M. D. et al. Clonal dynamics following p53 loss of heterozygosity in Kras-driven cancers. Nat. Commun. 7, 12685 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  192. Young, N. P. & Jacks, T. Tissue-specific p19Arf regulation dictates the response to oncogenic K-ras. Proc. Natl Acad. Sci. USA 107, 10184–10189 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Pin, C. L., Rukstalis, J. M., Johnson, C. & Konieczny, S. F. The bHLH transcription factor Mist1 is required to maintain exocrine pancreas cell organization and acinar cell identity. J. Cell Biol. 155, 519–530 (2001).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  194. Krapp, A. et al. The bHLH protein PTF1-p48 is essential for the formation of the exocrine and the correct spatial organization of the endocrine pancreas. Genes Dev. 12, 3752–3763 (1998).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  195. Shih, H. P. et al. A Notch-dependent molecular circuitry initiates pancreatic endocrine and ductal cell differentiation. Development 139, 2488–2499 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  196. Tompkins, D. H. et al. Sox2 is required for maintenance and differentiation of bronchiolar Clara, ciliated, and goblet cells. PLOS ONE 4, e8248 (2009).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  197. Shi, G. et al. Maintenance of acinar cell organization is critical to preventing Kras-induced acinar-ductal metaplasia. Oncogene 32, 1950–1958 (2013).

    Article  CAS  PubMed  Google Scholar 

  198. Shi, G. et al. Loss of the acinar-restricted transcription factor Mist1 accelerates Kras-induced pancreatic intraepithelial neoplasia. Gastroenterology 136, 1368–1378 (2009).

    Article  CAS  PubMed  Google Scholar 

  199. Krah, N. M. et al. The acinar differentiation determinant PTF1A inhibits initiation of pancreatic ductal adenocarcinoma. eLife 4, e07125 (2015).

    Article  PubMed Central  Google Scholar 

  200. Kopp, J. L. et al. Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. Cancer Cell 22, 737–750 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  201. Xu, X. et al. The cell of origin and subtype of K-Ras-induced lung tumors are modified by Notch and Sox2. Genes Dev. 28, 1929–1939 (2014).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  202. Tong, K. et al. Degree of tissue differentiation dictates susceptibility to BRAF-driven colorectal cancer. Cell Rep. 21, 3833–3845 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  203. Yuan, T. L. et al. Differential effector engagement by oncogenic KRAS. Cell Rep. 22, 1889–1902 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Zhao, Z. et al. Cooperative loss of RAS feedback regulation drives myeloid leukemogenesis. Nat. Genet. 47, 539–543 (2015).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  205. Kunimoto, H. et al. Cooperative epigenetic remodeling by TET2 loss and NRAS mutation drives myeloid transformation and MEK inhibitor sensitivity. Cancer Cell 33, 44–59.e8 (2018).

    Article  CAS  PubMed  Google Scholar 

  206. Stites, E. C., Trampont, P. C., Haney, L. B., Walk, S. F. & Ravichandran, K. S. Cooperation between noncanonical Ras network mutations. Cell Rep. 10, 307–316 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Vaz, M. et al. Chronic cigarette smoke-induced epigenomic changes precede sensitization of bronchial epithelial cells to single-step transformation by KRAS mutations. Cancer Cell 32, 360–376.e6 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  208. Sieber, O. M., Tomlinson, S. R. & Tomlinson, I. P. Tissue, cell and stage specificity of (epi)mutations in cancers. Nat. Rev. Cancer 5, 649–655 (2005).

    Article  CAS  PubMed  Google Scholar 

  209. Schneider, G., Schmidt-Supprian, M., Rad, R. & Saur, D. Tissue-specific tumorigenesis: context matters. Nat. Rev. Cancer 17, 239–253 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  210. Wellbrock, C., Karasarides, M. & Marais, R. The RAF proteins take centre stage. Nat. Rev. Mol. Cell Biol. 5, 875–885 (2004).

    Article  CAS  PubMed  Google Scholar 

  211. Chang, M. T. et al. Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity. Nat. Biotechnol. 34, 155–163 (2016).

    Article  CAS  PubMed  Google Scholar 

  212. Yao, Z. et al. Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS. Nature 548, 234–238 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  213. Morelli, M. P. et al. Characterizing the patterns of clonal selection in circulating tumor DNA from patients with colorectal cancer refractory to anti-EGFR treatment. Ann. Oncol. 26, 731–736 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  214. Yang, H. et al. Activated MEK cooperates with Cdkn2a and Pten loss to promote the development and maintenance of melanoma. Oncogene 36, 3842–3851 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  215. Su, F. et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N. Engl. J. Med. 366, 207–215 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgements

This work is supported by US National Cancer Institute (NCI) grants (R01CA123031, R01CA94184 and P01CA203657 to C.M.C. and UO1CA176287 and R35CA210018 to A.B.). The authors thank the reviewers for their extremely helpful suggestions. They also apologize to colleagues whose work could not be cited owning to a limitation on the number of references permitted in this article.

Author information

Authors and Affiliations

  1. Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA

    Siqi Li & Christopher M. Counter

  2. Helen Diller Family Comprehensive Cancer Center and Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA

    Allan Balmain

Authors
  1. Siqi Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Allan Balmain
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christopher M. Counter
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to researching data, discussing the content and writing, reviewing and editing of the article.

Corresponding author

Correspondence to Christopher M. Counter.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

Genotype-Tissue Expression (GTEx) Portal: https://gtexportal.org/home/

COSMIC: https://cancer.sanger.ac.uk/cosmic

Supplementary Information

Glossary

Codon

A three-nucleotide sequence coding for a specific amino acid.

DNA adducts

Segments of DNA covalently bound to a cancer-causing chemical moiety.

Expression quantitative trait locus

(eQTL). A genomic region that carries a DNA sequence variant that influences the expression level of a given gene.

Indels

Insertions or deletions of one or more DNA bases into a genome.

Lipidation

The addition of a lipid group to a peptide chain.

X-gal staining

An assay measuring the activity of β-galactosidase via the hydrolysis of X-gal and the generation of a blue-coloured product.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, S., Balmain, A. & Counter, C.M. A model for RAS mutation patterns in cancers: finding the sweet spot. Nat Rev Cancer 18, 767–777 (2018). https://doi.org/10.1038/s41568-018-0076-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41568-018-0076-6

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer