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Current Colorectal Cancer Reports

, Volume 7, Issue 2, pp 113–120 | Cite as

An Update on the Biology of RAS/RAF Mutations in Colorectal Cancer

  • Mandayam O. Nandan
  • Vincent W. YangEmail author
Article

Abstract

Deaths caused by colorectal cancer (CRC) are among the leading causes of cancer-related death in the United States and around the world. Approximately 150,000 Americans are diagnosed with CRC each year and around 50,000 will die from it. Mutations in many key genes have been identified that are important to the pathogenesis of CRC. Among the genes mutated in CRC, RAS and RAF mutations are common events. Both RAS and RAF are critical mediators of the mitogen-activated protein kinase (MAPK) pathway that is involved in regulating cellular homeostasis, including proliferation, survival, and differentiation. In this review, we provide a historical perspective and update on RAS/RAF mutations as related to colorectal cancer. Additionally, we will review recent mouse models of RAS and RAF mutations that have an impact on CRC research.

Keywords

RAS signaling pathway Oncogene Colorectal cancer KRAS and B-RAF mutations Mouse models 

Notes

Acknowledgment

This work was in part supported by grants from the National Institutes of Health (DK52230, DK64399, and CA84197).

Disclosure

No potential conflicts of interest relevant to this article were reported.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    •• Nandan MO, Yang VW. Genetic and chemical models of colorectal cancer in mice. Curr Colorectal Cancer Rep. 2010;6:51–9. This review article presents a compilation of different mouse models related to human CRC. Special emphasis is placed on important genetic mutations in human CRC. In addition, chemical models of CRC in mice are also explored.PubMedCrossRefGoogle Scholar
  2. 2.
    Malumbres M, Barbacid M. RAS oncogenes: the first 30 years. Nat Rev Cancer. 2003;3:459–65.PubMedCrossRefGoogle Scholar
  3. 3.
    Cox AD, Der CJ. Ras family signaling: therapeutic targeting. Cancer Biol Ther. 2002;1:599–606.PubMedGoogle Scholar
  4. 4.
    Mitin N, Rossman KL, Der CJ. Signaling interplay in Ras superfamily function. Curr Biol. 2005;15:R563–74.PubMedCrossRefGoogle Scholar
  5. 5.
    •• Harris TJ, McCormick F. The molecular pathology of cancer. Nat Rev Clin Oncol. 2010;7:251–65. The authors review the important clinical prognostic indicators of CRC with respect to genetic mutations. They also analyze the molecular changes in tumors that have helped in tailoring individualized therapies and treatments.PubMedCrossRefGoogle Scholar
  6. 6.
    Hayflick L. The limited in vitro lifetime of human diploid cell strains. Exp Cell Res. 1965;37:614–36.PubMedCrossRefGoogle Scholar
  7. 7.
    Harley CB, Futcher AB, Greider CW. Telomeres shorten during ageing of human fibroblasts. Nature. 1990;345:458–60.PubMedCrossRefGoogle Scholar
  8. 8.
    Shay JW, Wright WE, Werbin H. Defining the molecular mechanisms of human cell immortalization. Biochim Biophys Acta. 1991;1072:1–7.PubMedGoogle Scholar
  9. 9.
    Newbold RF, Overell RW. Fibroblast immortality is a prerequisite for transformation by EJ c-Ha-ras oncogene. Nature. 1983;304:648–51.PubMedCrossRefGoogle Scholar
  10. 10.
    Serrano M, Lin AW, McCurrach ME, et al. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997;88:593–602.PubMedCrossRefGoogle Scholar
  11. 11.
    Lin AW, Barradas M, Stone JC, et al. Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Genes Dev. 1998;12:3008–19.PubMedCrossRefGoogle Scholar
  12. 12.
    Zhu J, Woods D, McMahon M, et al. Senescence of human fibroblasts induced by oncogenic Raf. Genes Dev. 1998;12:2997–3007.PubMedCrossRefGoogle Scholar
  13. 13.
    •• Collado M, Serrano M. Senescence in tumours: evidence from mice and humans. Nat Rev Cancer. 2010;10:51–7. This is an outstanding review of senescence and its association in tumors. They provide evidence for senescence-deactivated malignant transformation of tumors. They also suggest a role for senescence in future drug therapeutics.PubMedCrossRefGoogle Scholar
  14. 14.
    Collado M, Blasco MA, Serrano M. Cellular senescence in cancer and aging. Cell. 2007;130:223–33.PubMedCrossRefGoogle Scholar
  15. 15.
    Forrester K, Almoguera C, Han K, et al. Detection of high incidence of K-ras oncogenes during human colon tumorigenesis. Nature. 1987;327:298–303.PubMedCrossRefGoogle Scholar
  16. 16.
    Kirsten WH, Mayer LA. Morphologic responses to a murine erythroblastosis virus. J Natl Cancer Inst. 1967;39:311–35.PubMedGoogle Scholar
  17. 17.
    Der CJ, Krontiris TG, Cooper GM. Transforming genes of human bladder and lung carcinoma cell lines are homologous to the ras genes of Harvey and Kirsten sarcoma viruses. Proc Natl Acad Sci USA. 1982;79:3637–40.PubMedCrossRefGoogle Scholar
  18. 18.
    Chang EH, Gonda MA, Ellis RW, et al. Human genome contains four genes homologous to transforming genes of Harvey and Kirsten murine sarcoma viruses. Proc Natl Acad Sci USA. 1982;79:4848–52.PubMedCrossRefGoogle Scholar
  19. 19.
    McCoy MS, Toole JJ, Cunningham JM, et al. Characterization of a human colon/lung carcinoma oncogene. Nature. 1983;302:79–81.PubMedCrossRefGoogle Scholar
  20. 20.
    McGrath JP, Capon DJ, Smith DH, et al. Structure and organization of the human Ki-ras proto-oncogene and a related processed pseudogene. Nature. 1983;304:501–6.PubMedCrossRefGoogle Scholar
  21. 21.
    Carta C, Pantaleoni F, Bocchinfuso G, et al. Germline missense mutations affecting KRAS Isoform B are associated with a severe Noonan syndrome phenotype. Am J Hum Genet. 2006;79:129–35.PubMedCrossRefGoogle Scholar
  22. 22.
    Koera K, Nakamura K, Nakao K, et al. K-ras is essential for the development of the mouse embryo. Oncogene. 1997;15:1151–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Esteban LM, Vicario-Abejon C, Fernandez-Salguero P, 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. 2001;21:1444–52.PubMedCrossRefGoogle Scholar
  24. 24.
    Reddy EP, Reynolds RK, Santos E, et al. A point mutation is responsible for the acquisition of transforming properties by the T24 human bladder carcinoma oncogene. Nature. 1982;300:149–52.PubMedCrossRefGoogle Scholar
  25. 25.
    Taparowsky E, Suard Y, Fasano O, et al. Activation of the T24 bladder carcinoma transforming gene is linked to a single amino acid change. Nature. 1982;300:762–5.PubMedCrossRefGoogle Scholar
  26. 26.
    Yuasa Y, Srivastava SK, Dunn CY, et al. Acquisition of transforming properties by alternative point mutations within c-bas/has human proto-oncogene. Nature. 1983;303:775–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Feig LA, Bast Jr RC, Knapp RC, et al. Somatic activation of rasK gene in a human ovarian carcinoma. Science. 1984;223:698–701.PubMedCrossRefGoogle Scholar
  28. 28.
    Shimizu K, Goldfarb M, Suard Y, et al. Three human transforming genes are related to the viral ras oncogenes. Proc Natl Acad Sci USA. 1983;80:2112–6.PubMedCrossRefGoogle Scholar
  29. 29.
    Winter E, Yamamoto F, Almoguera C, et al. A method to detect and characterize point mutations in transcribed genes: amplification and overexpression of the mutant c-Ki-ras allele in human tumor cells. Proc Natl Acad Sci USA. 1985;82:7575–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Hirai H, Kobayashi Y, Mano H, et al. A point mutation at codon 13 of the N-ras oncogene in myelodysplastic syndrome. Nature. 1987;327:430–2.PubMedCrossRefGoogle Scholar
  31. 31.
    Schubbert S, Zenker M, Rowe SL, et al. Germline KRAS mutations cause Noonan syndrome. Nat Genet. 2006;38:331–6.PubMedCrossRefGoogle Scholar
  32. 32.
    Bazan V, Migliavacca M, Zanna I, et al. Specific codon 13 K-ras mutations are predictive of clinical outcome in colorectal cancer patients, whereas codon 12 K-ras mutations are associated with mucinous histotype. Ann Oncol. 2002;13:1438–46.PubMedCrossRefGoogle Scholar
  33. 33.
    Heinemann V, Stintzing S, Kirchner T, et al. Clinical relevance of EGFR- and KRAS-status in colorectal cancer patients treated with monoclonal antibodies directed against the EGFR. Cancer Treat Rev. 2009;35:262–71.PubMedCrossRefGoogle Scholar
  34. 34.
    • Markman B, Javier Ramos F, Capdevila J, et al. EGFR and KRAS in colorectal cancer. Adv Clin Chem. 2010;51:71–119. This is an excellent review outlining the interplay and relevance between EGFR and KRAS mutations in CRC. It presents studies that have delineated the resistance to EGFR treatment in CRCs with mutated KRAS.PubMedCrossRefGoogle Scholar
  35. 35.
    Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:1626–34.PubMedCrossRefGoogle Scholar
  36. 36.
    Yen LC, Uen YH, Wu DC, et al. Activating KRAS mutations and overexpression of epidermal growth factor receptor as independent predictors in metastatic colorectal cancer patients treated with cetuximab. Ann Surg. 2010;251:254–60.PubMedCrossRefGoogle Scholar
  37. 37.
    Lee JK, Chan AT. Molecular prognostic and predictive markers in colorectal cancer: current status. Curr Colorectal Cancer Rep. 2011, in pressGoogle Scholar
  38. 38.
    Santelli G, de Franciscis V, Portella G, et al. Production of transgenic mice expressing the Ki-ras oncogene under the control of a thyroglobulin promoter. Cancer Res. 1993;53:5523–7.PubMedGoogle Scholar
  39. 39.
    Kim SH, Roth KA, Coopersmith CM, et al. Expression of wild-type and mutant simian virus 40 large tumor antigens in villus-associated enterocytes of transgenic mice. Proc Natl Acad Sci USA. 1994;91:6914–8.PubMedCrossRefGoogle Scholar
  40. 40.
    Johnson L, Mercer K, Greenbaum D, et al. Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature. 2001;410:1111–6.PubMedCrossRefGoogle Scholar
  41. 41.
    Lakso M, Sauer B, Mosinger Jr B, et al. Targeted oncogene activation by site-specific recombination in transgenic mice. Proc Natl Acad Sci USA. 1992;89:6232–6.PubMedCrossRefGoogle Scholar
  42. 42.
    Saam JR, Gordon JI. Inducible gene knockouts in the small intestinal and colonic epithelium. J Biol Chem. 1999;274:38071–82.PubMedCrossRefGoogle Scholar
  43. 43.
    Pinto D, Robine S, Jaisser F, et al. Regulatory sequences of the mouse villin gene that efficiently drive transgenic expression in immature and differentiated epithelial cells of small and large intestines. J Biol Chem. 1999;274:6476–82.PubMedCrossRefGoogle Scholar
  44. 44.
    Madison BB, Dunbar L, Qiao XT, et al. Cis elements of the villin gene control expression in restricted domains of the vertical (crypt) and horizontal (duodenum, cecum) axes of the intestine. J Biol Chem. 2002;277:33275–83.PubMedCrossRefGoogle Scholar
  45. 45.
    Ireland H, Kemp R, Houghton C, et al. Inducible Cre-mediated control of gene expression in the murine gastrointestinal tract: effect of loss of beta-catenin. Gastroenterology. 2004;126:1236–46.PubMedCrossRefGoogle Scholar
  46. 46.
    el Marjou F, Janssen KP, Chang BH, et al. Tissue-specific and inducible Cre-mediated recombination in the gut epithelium. Genesis. 2004;39:186–93.PubMedCrossRefGoogle Scholar
  47. 47.
    Janssen KP, el-Marjou F, Pinto D, et al. Targeted expression of oncogenic K-ras in intestinal epithelium causes spontaneous tumorigenesis in mice. Gastroenterology. 2002;123:492–504.PubMedCrossRefGoogle Scholar
  48. 48.
    Jackson EL, Willis N, Mercer K, et al. Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes Dev. 2001;15:3243–8.PubMedCrossRefGoogle Scholar
  49. 49.
    Tuveson DA, Shaw AT, Willis NA, et al. Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell. 2004;5:375–87.PubMedCrossRefGoogle Scholar
  50. 50.
    • Calcagno SR, Li S, Colon M, et al. Oncogenic K-ras promotes early carcinogenesis in the mouse proximal colon. Int J Cancer. 2008;122:2462–70. This is an important study that presents evidence of ACFs and early carcinogenesis in mice that express oncogenic KRAS in the intestinal epithelium driven by a Villin promoter. They suggest that KRAS mutations provide initiating thrust to neoplastic events in CRCs.PubMedCrossRefGoogle Scholar
  51. 51.
    Sansom OJ, Meniel V, Wilkins JA, 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. 2006;103:14122–7.PubMedCrossRefGoogle Scholar
  52. 52.
    Marais R, Light Y, Paterson HF, et al. Differential regulation of Raf-1, A-Raf, and B-Raf by oncogenic ras and tyrosine kinases. J Biol Chem. 1997;272:4378–83.PubMedCrossRefGoogle Scholar
  53. 53.
    Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–54.PubMedCrossRefGoogle Scholar
  54. 54.
    Rajagopalan H, Bardelli A, Lengauer C, et al. Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature. 2002;418:934.PubMedCrossRefGoogle Scholar
  55. 55.
    Gollob JA, Wilhelm S, Carter C, et al. Role of Raf kinase in cancer: therapeutic potential of targeting the Raf/MEK/ERK signal transduction pathway. Semin Oncol. 2006;33:392–406.PubMedCrossRefGoogle Scholar
  56. 56.
    •• Roberts PJ, Der CJ. Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene. 2007;26:3291–310. The authors provide a thorough analysis of the MAPK pathway starting from Ras. They detail the different mutations prevalent in cancers within this pathway and their inhibitors used in research.PubMedCrossRefGoogle Scholar
  57. 57.
    Wan PT, Garnett MJ, Roe SM, et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell. 2004;116:855–67.PubMedCrossRefGoogle Scholar
  58. 58.
    •• Karreth FA, Tuveson DA. Modelling oncogenic Ras/Raf signalling in the mouse. Curr Opin Genet Dev. 2009;19:4–11. This excellent review provides detail on mouse models on the MAPK pathway and its mutations. The authors have given special emphasis to oncogenic RAS and RAF models.PubMedCrossRefGoogle Scholar
  59. 59.
    Mercer K, Giblett S, Green S, et al. Expression of endogenous oncogenic V600EB-raf induces proliferation and developmental defects in mice and transformation of primary fibroblasts. Cancer Res. 2005;65:11493–500.PubMedCrossRefGoogle Scholar
  60. 60.
    Dankort D, Filenova E, Collado M, et al. A new mouse model to explore the initiation, progression, and therapy of BRAFV600E-induced lung tumors. Genes Dev. 2007;21:379–84.PubMedCrossRefGoogle Scholar
  61. 61.
    • Kamata T, Hussain J, Giblett S, et al. BRAF inactivation drives aneuploidy by deregulating CRAF. Cancer Res. 2010;70:8475–86. This study relates mutation in B-RAF gene with the activation of C-RAF, along with MEK/ERK, and subsequently aneuploidy.PubMedCrossRefGoogle Scholar
  62. 62.
    Noble C, Mercer K, Hussain J, et al. CRAF autophosphorylation of serine 621 is required to prevent its proteasome-mediated degradation. Mol Cell. 2008;31:862–72.PubMedCrossRefGoogle Scholar
  63. 63.
    Garnett MJ, Rana S, Paterson H, et al. Wild-type and mutant B-RAF activate C-RAF through distinct mechanisms involving heterodimerization. Mol Cell. 2005;20:963–9.PubMedCrossRefGoogle Scholar
  64. 64.
    Heidorn SJ, Milagre C, Whittaker S, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell. 2010;140:209–21.PubMedCrossRefGoogle Scholar
  65. 65.
    • Poulikakos PI, Zhang C, Bollag G, et al. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature. 2010;464:427–30. This exceptional study reports the activation of one protomer of the RAF hetero/homodimers upon deactivation of the other protomer due to drug binding. They suggest a model for RAF/RAS activation in tumors in the presence of a RAF inhibitor.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Division of Digestive Diseases, Department of MedicineEmory University School of MedicineAtlantaUSA
  2. 2.Department of Hematology and Medical OncologyEmory University School of MedicineAtlantaUSA

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