Skip to main content

Advertisement

SpringerLink
Log in

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

  • LAB INVESTIGATION
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Riccardi VM (1981) Von Recklinghausen neurofibromatosis. N Engl J Med 305:1617–1627

    Article  PubMed  CAS  Google Scholar 

  2. Rosenbaum T, Patrie KM, Ratner N (1997) Neurofibromatosis type 1: genetic and cellular mechanisms of peripheral nerve tumor formation. Neuroscientist 3:412–420

    Article  CAS  Google Scholar 

  3. DeVita Jr VT, Hellman S, Rosenberg SA (eds) (2004) Principles and practice of oncology, 7th edn. Lippincott Williams & Wilkins, Philadelphia

  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 4:83–101

    Article  PubMed  CAS  Google Scholar 

  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 12:507–513

    PubMed  CAS  Google Scholar 

  6. Carpenter G, Cohen S (1979) Epidermal growth factor. Ann Rev Biochem 48:193–216

    Article  PubMed  CAS  Google Scholar 

  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 100:707–725

    PubMed  CAS  Google Scholar 

  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 233:1079–1082

    Article  Google Scholar 

  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 105:1233–1241

    Article  PubMed  CAS  Google Scholar 

  10. Kitano Y, Okamoto E, Saito K, Okano Y (1992) Effects of several growth factors on cultured neurofibroma cells. J Dermatol Sci 3:137–144

    Article  PubMed  CAS  Google Scholar 

  11. Dugoff L, Sujansky E (1996) Neurofibromatosis type 1 and pregnancy. Am J Med Genet 66:7–10

    Article  PubMed  CAS  Google Scholar 

  12. Tsutsumi O, Oka T (1987) Epidermal growth factor deficiency during pregnancy causes abortion in mice. Am J Obstet Gynecol 156:241–244

    PubMed  CAS  Google Scholar 

  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 41:245–249

    PubMed  CAS  Google Scholar 

  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 359:397–401

    Article  PubMed  CAS  Google Scholar 

  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 64:1220–1223

    Article  PubMed  CAS  Google Scholar 

  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 278:51–57

    Article  PubMed  CAS  Google Scholar 

  17. Riccardi VM, Eichner JE (1992) Neurofibromatosis: phenotype, natural history and pathogenesis, 2nd edn. Johns Hopkins University Press, Baltimore

  18. Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215

    Article  PubMed  CAS  Google Scholar 

  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 107:673–675

    Article  PubMed  CAS  Google Scholar 

  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 64:2668–2672

    Article  PubMed  CAS  Google Scholar 

  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 123:760–762

    Article  PubMed  CAS  Google Scholar 

  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 123:755–759

    Article  PubMed  CAS  Google Scholar 

  23. Sorensen SA, Mulvihill JJ, Nielsen A (1986) Long-term follow-up of Von Recklinghausen neurofibromatosis. N Engl J Med 314:1010–1015

    Article  PubMed  CAS  Google Scholar 

  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 79:2125–2131

    Article  PubMed  CAS  Google Scholar 

  25. Harris RC, Chung E, Coffey RJ (2003) EGF receptor ligands. Exp Cell Res 284:2–13

    Article  CAS  Google Scholar 

  26. Peyssonnaux C, Eychene A (2001) The Raf/MEK/ERK pathway: new concepts of activation. Biol Cell 93:53–62

    Article  PubMed  CAS  Google Scholar 

  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 62:6451–6455

    PubMed  CAS  Google Scholar 

  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 63:4878–4881

    Google Scholar 

  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) 105:323–330

    Article  CAS  Google Scholar 

  30. Ellis DL, King LE Jr, Nanney LB (1992) Increased epidermal growth factor receptors in melanocytic lesions. J Am Acad Dermatol 27:539–546

    Article  PubMed  CAS  Google Scholar 

  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 56:853–857

    Article  PubMed  CAS  Google Scholar 

  32. Korakawa K, Makita T (1977) Histopathologic study of small iris nodules associated with von Recklinghausen disease. Jap Folia Ophtal 28:1289–1295

    Google Scholar 

  33. Lubs ML, Bauer MS, Formas ME, Djokic B (1991) Lisch nodules in neurofibromatosis type 1. N Engl J Med 324:1264–1266

    Article  PubMed  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Molecular Oncology—CI, Portuguese Institute of Oncology, Edifício Laboratórios—PISO 4, R. Dr. Ant. Bernardino Almeida, 4200-072, Porto, Portugal

    Ricardo Ribeiro, Daniela Pinto, Raquel Catarino, Carlos Lopes & Rui Medeiros

  2. Neurology Department, Portuguese Institute of Oncology, Porto, Portugal

    Ângelo Soares

  3. ICBAS, Abel Salazar Institute for the Biomedical Sciences, University of Porto, Porto, Portugal

    Ricardo Ribeiro, Carlos Lopes & Rui Medeiros

Authors
  1. Ricardo Ribeiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ângelo Soares
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daniela Pinto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Raquel Catarino
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Carlos Lopes
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rui Medeiros
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rui Medeiros.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ribeiro, R., Soares, Â., Pinto, D. et al. EGF genetic polymorphism is associated with clinical features but not malignant phenotype in neurofibromatosis type 1 patients. J Neurooncol 81, 225–229 (2007). https://doi.org/10.1007/s11060-006-9224-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-006-9224-z

Keywords

Search

Navigation