Advertisement

Journal of Neuro-Oncology

, Volume 81, Issue 3, pp 225–229 | Cite as

EGF genetic polymorphism is associated with clinical features but not malignant phenotype in neurofibromatosis type 1 patients

  • Ricardo Ribeiro
  • Ângelo Soares
  • Daniela Pinto
  • Raquel Catarino
  • Carlos Lopes
  • Rui Medeiros
LAB INVESTIGATION

Abstract

Neurofibromatosis type 1 (NF1) is characterized by a wide variation in clinical presentation and in some cases progression to malignant tumor. Epidermal growth factor (EGF) is an important mitogen for Schwann cells and is involved in the development of malignant tumors in NF1 patients. We hypothesized that EGF +61 G/A functional polymorphism, which represents constitutional all-life exposure to higher EGF expression and circulating levels, may predispose for precocious and more aggressive manifestations of disease. We found that clinical findings of intestinal polyps are significantly more frequent in patients with G homozygous genotype (P = 0.023). Those carriers of GG genotype have earlier onset of café-au-lait spots and Lisch nodules appearance (P = 0.030 and P = 0.017, respectively). Nevertheless, the EGF overexpressing genotype—GG, is not associated with higher risk for malignant progression or severity of disease. EGF polymorphism may play a role in the earlier onset of NF1 pigment cell-related manifestations and in intestinal polyps’ development. Further studies in larger samples should confirm the absence of risk for having higher severity grade or malignant phenotype in NF1 patients.

Keywords

Clinical characteristics EGF Neurofibromatosis type 1 PCR–RFLP Polymorphism 

Notes

Acknowledgements

We gratefully acknowledge funding of this work by the Minister of Health of Portugal (Comissão de Fomento da Investigação em Cuidados de Saúde: CFICS-226/01). The authors would like to thank the Liga Portuguesa Contra o Cancro- Centro Regional do Norte (Portuguese League Against Cancer) and Fundação Astra Zeneca, for their support.

References

  1. 1.
    Riccardi VM (1981) Von Recklinghausen neurofibromatosis. N Engl J Med 305:1617–1627PubMedCrossRefGoogle Scholar
  2. 2.
    Rosenbaum T, Patrie KM, Ratner N (1997) Neurofibromatosis type 1: genetic and cellular mechanisms of peripheral nerve tumor formation. Neuroscientist 3:412–420CrossRefGoogle Scholar
  3. 3.
    DeVita Jr VT, Hellman S, Rosenberg SA (eds) (2004) Principles and practice of oncology, 7th edn. Lippincott Williams & Wilkins, PhiladelphiaGoogle Scholar
  4. 4.
    Upadhyaya M, Shaw DJ, Harper PS (1994) Molecular basis of neurofibromatosis type 1 (NF1): mutation analysis and polymorphisms in the NF1 gene. Hum Mut 4:83–101PubMedCrossRefGoogle Scholar
  5. 5.
    Guha A, Lau N, Huvar I, Gutmann D, Provias J, Pawson T, Boss G (1996) Ras-GTP levels are elevated in human NF1 peripheral nerve tumors. Oncogene 12:507–513PubMedGoogle Scholar
  6. 6.
    Carpenter G, Cohen S (1979) Epidermal growth factor. Ann Rev Biochem 48:193–216PubMedCrossRefGoogle Scholar
  7. 7.
    Sundell H, Gray H, Serenius F, Escobedo MB, Stahlman MT (1980) Effects of epidermal growth factor on lung maturation in fetal lambs. Am J Pathol 100:707–725PubMedGoogle Scholar
  8. 8.
    Marquardt H, Hunkapillar MW, Hood LE, Todaro GJ (1984) Rat transforming growth factor factor type 1: structure and relation to epidermal growth factor. Science 233:1079–1082CrossRefGoogle Scholar
  9. 9.
    DeClue JE, Heffelfinger S, Benvenuto G, Ling B, Li S, Rui W, Vass WC, Viskochil D, Ratner N (2000) Epidermal growth factor receptor expression in neurofibromatosis type 1-related tumors and NF1 animal models. J Clin Invest 105:1233–1241PubMedCrossRefGoogle Scholar
  10. 10.
    Kitano Y, Okamoto E, Saito K, Okano Y (1992) Effects of several growth factors on cultured neurofibroma cells. J Dermatol Sci 3:137–144PubMedCrossRefGoogle Scholar
  11. 11.
    Dugoff L, Sujansky E (1996) Neurofibromatosis type 1 and pregnancy. Am J Med Genet 66:7–10PubMedCrossRefGoogle Scholar
  12. 12.
    Tsutsumi O, Oka T (1987) Epidermal growth factor deficiency during pregnancy causes abortion in mice. Am J Obstet Gynecol 156:241–244PubMedGoogle Scholar
  13. 13.
    Morton CC, Byers MG, Nakai H, Bell GI, Shows TB (1986) Human genes for insulin-like growth factors I and II and epidermal growth factor are located on 12q22→q24.1, 11p15, and 4q25→q27, respectively. Cytogenet Cell Genet 41:245–249PubMedGoogle Scholar
  14. 14.
    Shahbazi M, Pravica V, Nasreen N, Fakhoury H, Fryer AA, Strange RC, Hutchinson PE, Osborne JE, Lear JT, Smith AG, Hutchinson IV (2002) Association between functional polymorphism in EGF gene and malignant melanoma. Lancet 359:397–401PubMedCrossRefGoogle Scholar
  15. 15.
    Bhowmick DA, Zhuang Z, Wait SD, Weil RJ (2004) A functional polymorphism in the EGF gene is found with increased frequency in glioblastoma multiforme patients and is associated with more aggressive disease. Cancer Res 64:1220–1223PubMedCrossRefGoogle Scholar
  16. 16.
    Gutmann DH, Aylsworth A, Carey JC, Korf B, Marks J, Pyeritz RE, Rubenstein A, Viskochil D (1997) The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA 278:51–57PubMedCrossRefGoogle Scholar
  17. 17.
    Riccardi VM, Eichner JE (1992) Neurofibromatosis: phenotype, natural history and pathogenesis, 2nd edn. Johns Hopkins University Press, BaltimoreGoogle Scholar
  18. 18.
    Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215PubMedCrossRefGoogle Scholar
  19. 19.
    McCarron SL, Bateman AC, Theaker JM, Howell WM (2003) EGF +61 gene polymorphism and susceptibility to and prognostic markers in cutaneous malignant melanoma. Int J Cancer 107:673–675PubMedCrossRefGoogle Scholar
  20. 20.
    Amend KL, Elder JT, Tomsho LP, Bonner JD, Johnson TM, Schwartz J, Berwick M, Gruber SB (2004) EGF gene polymorphism and the risk of incident primary melanoma. Cancer Res 64:2668–2672PubMedCrossRefGoogle Scholar
  21. 21.
    James MR, Hayward NK, Dumenil T, Montgomery GW, Martin NG, Duffy DL (2004) Epidermal growth factor gene (EGF) polymorphism and risk of melanocytic neoplasia. J Invest Dermatol 123:760–762PubMedCrossRefGoogle Scholar
  22. 22.
    Randerson-Moor JA, Gaut R, Turner F, Whitaker L, Barrett JH, Dos Santos Silva I, Swerdlow A, Bishop DT, Newton Bishop JA (2004) The relationship between the Epidermal growth factor (EGF) 5′UTR variant A61G and melanoma/nevus susceptibility. J Invest Dermatol 123:755–759PubMedCrossRefGoogle Scholar
  23. 23.
    Sorensen SA, Mulvihill JJ, Nielsen A (1986) Long-term follow-up of Von Recklinghausen neurofibromatosis. N Engl J Med 314:1010–1015PubMedCrossRefGoogle Scholar
  24. 24.
    Zoller ME, Rembeck B, Odén A, Samuelsson M, Angervall L (1997) Malignant and benign tumors in patients with neurofibromatosis type 1 in a defined Swedish population. Cancer 79:2125–2131PubMedCrossRefGoogle Scholar
  25. 25.
    Harris RC, Chung E, Coffey RJ (2003) EGF receptor ligands. Exp Cell Res 284:2–13CrossRefGoogle Scholar
  26. 26.
    Peyssonnaux C, Eychene A (2001) The Raf/MEK/ERK pathway: new concepts of activation. Biol Cell 93:53–62PubMedCrossRefGoogle Scholar
  27. 27.
    Yuen ST, Davies H, Chan TL, Ho JW, Bignell GR, Cox C, Stephens P, Edkins S, Tsui WW, Chan AS, Futreal PA, Stratton MR, Wooster R, Leung SY (2002) Similarity of the phenotypic patterns associated with BRAF and KRAS mutations in colorectal neoplasia. Cancer Res 62:6451–6455PubMedGoogle Scholar
  28. 28.
    Chan TL, Zhao W, Cancer Genome Project, Leung SY, Yuen ST (2003) BRAF and KRAS mutations in colorectal hyperplastic polyps and serrated adenomas. Cancer Res 63:4878–4881Google Scholar
  29. 29.
    Bashir O, Fitzgerald AJ, Berlanga-Acosta J, Playford RJ, Goodlad RA (2003) Effect of epidermal growth factor administration on intestinal cell proliferation, crypt fission and polyp formation in multiple intestinal neoplasia (Min) mice. Clin Sci (Lond) 105:323–330CrossRefGoogle Scholar
  30. 30.
    Ellis DL, King LE Jr, Nanney LB (1992) Increased epidermal growth factor receptors in melanocytic lesions. J Am Acad Dermatol 27:539–546PubMedCrossRefGoogle Scholar
  31. 31.
    Mattei S, Colombo MP, Melani C, Silvani A, Parmiani G, Herlyn M (1994) Expression of cytokine/growth factors and their receptors in human melanoma and melanocytes. Int J Cancer 56:853–857PubMedCrossRefGoogle Scholar
  32. 32.
    Korakawa K, Makita T (1977) Histopathologic study of small iris nodules associated with von Recklinghausen disease. Jap Folia Ophtal 28:1289–1295Google Scholar
  33. 33.
    Lubs ML, Bauer MS, Formas ME, Djokic B (1991) Lisch nodules in neurofibromatosis type 1. N Engl J Med 324:1264–1266PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2006

Authors and Affiliations

  • Ricardo Ribeiro
    • 1
    • 3
  • Ângelo Soares
    • 2
  • Daniela Pinto
    • 1
  • Raquel Catarino
    • 1
  • Carlos Lopes
    • 1
    • 3
  • Rui Medeiros
    • 1
    • 3
  1. 1.Molecular Oncology—CIPortuguese Institute of OncologyPortoPortugal
  2. 2.Neurology Department Portuguese Institute of OncologyPortoPortugal
  3. 3.ICBAS, Abel Salazar Institute for the Biomedical SciencesUniversity of PortoPortoPortugal

Personalised recommendations