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.

  • Oncogenomics
  • Published:

H-RAS 81 polymorphism is significantly associated with aneuploidy in follicular tumors of the thyroid

Oncogene volume 25, pages 4620–4627 (2006)Cite this article

Abstract

Follicular thyroid tumors are often aneuploid. It was advanced that chromosomal instability is closely associated to RAS mutations, but such association remains unproven. H-RAS can be alternatively spliced in two different proteins, p21 and p19, the former being the active protein. In order to investigate the relationship between RAS mutational status and ploidy in thyroid tumors, we analysed RAS genes in a series of 99 follicular lesions (14 nodular goiters, 70 follicular adenomas and 15 follicular carcinomas), eight thyroid carcinoma cell lines and a control group of 102 blood donors, correlating the presence of RAS mutations with the ploidy of the tumors and evaluating the two spliced forms of H-RAS. Overall, 20% of the follicular tumors harbored RAS mutations and 62% of the patients with follicular tumors (and 51% of blood donors) harbored the H-RAS 81T → C polymorphism. The presence of RAS mutations was not associated with aneuploidy. The H-RAS polymorphism did not seem to confer a higher propensity for neoplastic transformation as it was also found in hyperplastic lesions, but was strongly associated with aneuploidy (P<0.0001). The presence of the H-RAS 81T → C polymorphism was associated with significantly higher amounts of total H-RAS mRNA expression, higher amounts of p21 isoform and a higher fraction of neoplastic cells in S phase. Our results suggest that the H-RAS 81T → C polymorphism may induce aneuploidy through overexpression of the active p21 isoform of H-RAS.

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

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  • Bos JL . (1989). Cancer Res 49: 4682–4689.

  • Castro P, Eknaes M, Teixeira MR, Danielsen HE, Soares P, Lothe RA et al. (2005). J Pathol 206: 305–311.

  • Castro P, Sansonetty F, Soares P, Dias A, Sobrinho-Simoes M . (2001). Virchows Arch 438: 336–342.

  • Codony C, Guil S, Caudevilla C, Serra D, Asins G, Graessmann A et al. (2001). Oncogene 20: 3683–3694.

  • Cohen JB, Broz SD, Levinson AD . (1989). Cell 58: 461–472.

  • Cohen JB, Broz SD, Levinson AD . (1993). Mol Cell Biol 13: 2666–2676.

  • Coleman ML, Marshall CJ, Olson MF . (2004). Nat Rev Mol Cell Biol 5: 355–366.

  • Cusick EL, Ewen SW, Krukowski ZH, Matheson NA . (1991). Br J Surg 78: 94–96.

  • Deitch AD, Law H, White RD . (1982). J Histochem Cytochem 30: 967–972.

  • DeLellis RA, Lloyd RV, Heitz PU, Eng C (eds) (2004). Pathology and Genetics of Tumours of Endocrine Organs. IARC Press: USA.

    Google Scholar 

  • Denko N, Stringer J, Wani M, Stambrook P . (1995). Somat Cell Mol Genet 21: 241–253.

  • Denko NC, Giaccia AJ, Stringer JR, Stambrook PJ . (1994). Proc Natl Acad Sci USA 91: 5124–5128.

  • Esapa CT, Johnson SJ, Kendall-Taylor P, Lennard TW, Harris PE . (1999). Clin Endocrinol (Oxford) 50: 529–535.

  • Fagin JA . (2002). Mol Endocrinol 16: 903–911.

  • Feramisco JR, Gross M, Kamata T, Rosenberg M, Sweet RW . (1984). Cell 38: 109–117.

  • Giaretti W, Molinu S, Ceccarelli J, Prevosto C . (2004). Cell Oncol 26: 301–305.

  • Giaretti W, Pujic N, Rapallo A, Nigro S, Di Vinci A, Geido E et al. (1995). Gastroenterology 108: 1040–1047.

  • Giaretti W, Rapallo A, Geido E, Sciutto A, Merlo F, Risio M et al. (1998). Am J Pathol 153: 1201–1209.

  • Guil S, de La Iglesia N, Fernandez-Larrea J, Cifuentes D, Ferrer JC, Guinovart JJ et al. (2003a). Cancer Res 63: 5178–5187.

  • Guil S, Gattoni R, Carrascal M, Abian J, Stevenin J, Bach-Elias M . (2003b). Mol Cell Biol 23: 2927–2941.

  • Hara H, Fulton N, Yashiro T, Ito K, DeGroot LJ, Kaplan EL . (1994). Surgery 116: 1010–1016.

  • Hostetter AL, Hrafnkelsson J, Wingren SOW, Enestrom S, Nordenskjöld B . (1988). Am J Clin Pathol 89: 760–763.

  • Huang MY, Cohen JB . (1997). Oncol Res 9: 611–621.

  • Illmer T, Thiede C, Fredersdorf A, Stadler S, Neubauer A, Ehninger G et al. (2005). Clin Cancer Res 11: 3217–3224.

  • Joensuu H, Klemi PJ . (1988). Am J Clin Pathol 89: 35–40.

  • Johannessen JV, Sobrinho-Simões M, Tangen KO . (1982). Am J Clin Pathol 77: 20–25.

  • Johne A, Roots I, Brockmoller J . (2003). Epidemiol Biomarkers Prev 12: 68–70.

  • Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE, Fagin JA . (2003). Cancer Res 63: 1454–1457.

  • Krontiris TG, Devlin B, Karp DD, Robert NJ, Risch N . (1993). N Engl J Med 329: 517–523.

  • Liwo A, Gibson KD, Scheraga HA, Brandt-Rauf PW, Monaco R, Pincus MR . (1994). J Protein Chem 13: 237–251.

  • Mammas IN, Zafiropoulos A, Koumantakis E, Sifakis S, Spandidos DA . (2004). Gynecol Oncol 92: 941–948.

  • Mascaux C, Iannino N, Martin B, Paesmans M, Berghmans T, Dusart M et al. (2005). Br J Cancer 92: 131–139.

  • Monaco R, Chen JM, Chung D, Brandt-Rauf P, Pincus MR . (1995). J Protein Chem 14: 457–466.

  • Mulcahy LS, Smith MR, Stacey DW . (1985). Nature 313: 241–243.

  • Nikiforova MN, Lynch RA, Biddinger PW, Alexander EK, Dorn II GW, Tallini G et al. (2003). J Clin Endocrinol Metab 88: 2318–2326.

  • Noonan T, Brown N, Dudycz L, Wright G . (1991). J Med Chem 34: 1302–1307.

  • Pastinen T, Hudson TJ . (2004). Science 306: 647–650.

  • Pulciani S, Santos E, Long LK, Sorrentino V, Barbacid M . (1985). Mol Cell Biol 5: 2836–2841.

  • Rosai J, Carcangiu ML, DeLellis RA . (1993). Tumors of the Thyroid Gland (Atlas of tumor pathology, 3rd series, fascicle 5) Armed forces Isntitute of Pathology: Washington, DC.

    Google Scholar 

  • Saavedra HI, Knauf JA, Shirokawa JM, Wang J, Ouyang B, Elisei R et al. (2000). Oncogene 19: 3948–3954.

  • Schelfhout LJ, Cornelisse CJ, Goslings BM, Hamming JF, Kuipers-Dijkshoorn NJ, van de Velde CJ et al. (1990). Int J Cancer 45: 16–20.

  • Schneider S, Roessli D, Excoffier L . (2000). Arlequin: a software for population genetics data analysis. Genetics and Biometry Lab, Department of Anthropology, University of Geneva.

    Google Scholar 

  • Soares P, Trovisco V, Rocha AS, Lima J, Castro P, Preto A et al. (2003). Oncogene 22: 4578–4580.

  • Sugg SL, Ezzat S, Zheng L, Freeman JL, Rosen IB, Asa SL . (1999). Surgery 125: 46–52.

  • Tabin CJ, Bradley SM, Bargmann CI, Weinberg RA, Papageorge AG, Scolnick EM et al. (1982). Nature 300: 143–149.

  • Wang B, Soule HD, Miller FR . (1997). Anticancer Res 17: 4387–4394.

Download references

Acknowledgements

This study was partially supported by a PhD grant (SFRH/BD/6816/2001 – PC) from the Portuguese Science and Technology Foundation (FCT) and with further funding from the same source (Project – ‘Programa Operacional Ciência Tecnologia e Inovação/Ciências Biomédicas e Oncológicas/338567/2001’). Cell lines were kindly provided by David Wynford-Thomas, Jacques E Dumont, Marc Mareel, Massimo Santoro and F Savagner.

Author information

Authors and Affiliations

  1. Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal

    P Castro, P Soares, L Gusmão, R Seruca & M Sobrinho-Simões

  2. Department of Pathology, Medical Faculty of Porto, Porto, Portugal

    P Soares, R Seruca & M Sobrinho-Simões

Authors
  1. P Castro
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P Soares
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L Gusmão
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R Seruca
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M Sobrinho-Simões
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M Sobrinho-Simões.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Castro, P., Soares, P., Gusmão, L. et al. H-RAS 81 polymorphism is significantly associated with aneuploidy in follicular tumors of the thyroid. Oncogene 25, 4620–4627 (2006). https://doi.org/10.1038/sj.onc.1209491

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1209491

Keywords

This article is cited by

Search

Advanced search

Quick links