Skip to main content
SpringerLink
Log in

Non-hyperfunctioning nodules from multinodular goiters: A minor role in pathogenesis for somatic activating mutations in the TSH-receptor and Gsα subunit genes

  • Original Article
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Constitutive activation of the cAMP pathway stimulates thyrocyte proliferation. Gainof-function mutations in Gsα protein have already been identified in thyroid nodules which have lost the ability to trap iodine. In contrast, most of the studies failed to detect somatic activating mutations in the thyrotropin receptor (TSH-R) in non-hyperfunctioning thyroid tumors. The aim of this study was to screen for mutations TSH-R exon 10, encoding the whole intracytoplasmic area involved in signal transduction, and Gsα exons 8 and 9, containing the two hot-spot codons 201 and 227, in a subset of non-hyperfunctioning nodules from multinodular goiter. Identified by matching ultrasonography and scintiscan, 22 eufunctioning (normal 99Tc uptake) and 15 nonfunctioning (decreased 99Tc uptake) nodules from 27 non-toxic multinodular goiters were isolated. After DNA extraction, TSH-R exon 10 was analyzed by direct sequencing of the PCR products and Gsα exons 8 and 9 by Denaturing Gradient Gel Electrophoresis. No mutation of TSH-R or Gsα was detected in the 37 nodules analyzed. This absence of mutation, despite the use of two sensitive screening methods associated with the analysis of the TSH-R whole intracytoplasmic area and Gsα two hot-spot codons, suggests that TSH-R and Gsα play a minor role in the pathogenesis of non-toxic nodules from multinodular goiters.

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. Vassart G., Dumont J.E. The thyrotropin receptor and the regulation of thyrocyte function and growth. Endocr. Rev. 1992, 13: 596–611.

    CAS  PubMed  Google Scholar 

  2. Paschke R., Ludgate M. The thyrotropin receptor in thyroid diseases. N. Engl. J. Med. 1997, 337: 1675–1681.

    Article  CAS  PubMed  Google Scholar 

  3. Murakami M., Kamyia Y., Yanagita Y., Mori M. Gsα mutations in hyperfunctioning thyroid adenomas. Arch. Med. Res. 1999, 30: 514–521.

    Article  CAS  PubMed  Google Scholar 

  4. Matsuo K., Friedman E., Gejman P.V., Fagin J.A. The thyrotropin receptor (TSH-R) is not an oncogene for thyroid tumors: structural studies of the TSH-R and the α-subunit of Gs in human thyroid neoplasms. J. Clin. Endocrinol. Metab. 1993, 76: 1446–1451.

    CAS  PubMed  Google Scholar 

  5. Spambalg D., Sharifi N., Elisei R., Gross J.L., Medeiros-Neto G., Fagin A.G. Structural studies of the thyrotropin receptor and Gsα in human thyroid cancers: low prevalence of mutations predicts infrequent involvement in malignant transformation. J. Clin. Endocrinol. Metab. 1996, 81: 3898–3901.

    CAS  PubMed  Google Scholar 

  6. Esapa C., Foster S., Johnson S., Jameson L., Kendall-Taylor P., Harris P.E. G protein and thyrotropin receptor mutations in thyroid neoplasia. J. Clin. Endocrinol. Metab. 1997, 82: 493–496.

    CAS  PubMed  Google Scholar 

  7. Tonacchera M., Vitti P., Agretti P., Ceccarini G., Perri A., Cavaliere R., Mazzi B., Naccarato A.G., Viacava P., Miccoli P., Pinchera A., Chiovato L. Functioning and nonfunctioning thyroid adenomas involve different molecular pathogenetic mechanisms. J. Clin. Endocrinol. Metab. 1999, 84: 4155–4158.

    CAS  PubMed  Google Scholar 

  8. Tonacchera M., Cetani F., Parma J., Van Sande J., Vassart G., Dumont J. Oncogenic mutations in thyroid adenoma: methodological criteria. Eur. J. Endocrinol. 1996, 135: 444–446.

    Article  CAS  PubMed  Google Scholar 

  9. Ludgate M., Gire V., Crisp M., Ajjan R., Weetman A., Ivan M., Wynford-Thomas D. Contrasting effects of activating mutations of Gsα and the thyrotropin receptor on proliferation and differentiation of thyroid follicular cells. Oncogene 1999, 18: 4798–4807.

    Article  CAS  PubMed  Google Scholar 

  10. Van Sande J., Parma J., Tonacchera M., Swillens S., Dumont J., Vassart G. Genetic basis of endocrine disease: somatic and germline mutations of the TSH receptor gene in thyroid diseases. J. Clin. Endocrinol. Metab. 1995, 80: 2577–2585.

    PubMed  Google Scholar 

  11. Yoshimoto K., Iwahana H., Fukuda A., Sano T., Itakura M. Mutation detection by polymerase chain reaction-primer-introduced restriction analysis. Cancer 1993, 72: 1386–1393.

    Article  CAS  PubMed  Google Scholar 

  12. Saïd S., Schlumberger M., Suarez H.G. Oncogenes and anti-oncogenes in human epithelial thyroid tumors. J. Endocrinol. Invest. 1994, 17: 371–379.

    Article  PubMed  Google Scholar 

  13. Horie H., Yokogoshi Y., Tsuyuguchi M., Saito S. Point mutations of ras and Gsα subunit genes in thyroid tumors. Jpn. J. Cancer Res. 1995, 86: 737–742.

    Article  CAS  PubMed  Google Scholar 

  14. Wyman A.R., White R. A highly polymorphic locus in human DNA. Proc. Natl. Acad. Sci. USA 1980, 77: 6754–6758.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Sanger F., Nicklen S., Coulson A.R. DNA sequencing with chain-terminating inhibitors. Proc. Natl. Acad. Sci. USA 1977, 74: 5463–5467.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Nagayama Y., Kaufman K.D., Seto P., Rapoport B. Molecular cloning, sequence and functional expression of the cDNA for the human thyrotropin receptor. Biochem. Biophys. Res. Commun. 1989, 165: 1184–1190.

    Article  CAS  PubMed  Google Scholar 

  17. Myers R., Fisher S.G., Lerman L.S., Maniatis T. Nearly all single base substitution in DNA fragments joined to a GC clamp can be detected by denaturating gradient gel electrophoresis. Nucleic Acids Res. 1995, 13: 3131–3145.

    Article  Google Scholar 

  18. Lyons J., Landis C.A., Harsh G., Vallar L., Grünewald K., Feichtinger H., Duh Q.Y., Clark O.H., Kawasaki E., Bourne H.R., Mc Cormick F. Two G protein oncogenes in human endocrine tumors. Science 1990, 249: 655–659.

    Article  CAS  PubMed  Google Scholar 

  19. Duprez L., Hermans J., Van Sande J., Dumont J.E., Vassart G., Parma J. Two autonomous nodules of a patient with multinodular goiter harbor different activating mutations of the thyrotropin receptor gene. J. Clin. Endocrinol. Metab. 1997, 82: 306–308.

    CAS  PubMed  Google Scholar 

  20. Holzapfel H.P., Führer D., Wonerow P., Weinland G., Scherbaum W.A., Paschke R. Identification of constitutively activating somatic thyrotropin receptor mutations in a subset of toxic multinodular goiters. J. Clin. Endocrinol. Metab. 1997, 82: 4229–4233.

    CAS  PubMed  Google Scholar 

  21. Tonacchera M., Vitti P., Agretti P., Giulianetti B., Mazzi B., Cavaliere R., Ceccarini G., Fiore E., Viacava P., Naccarato A., Pinchera A., Chiovato L. Activating thyrotropin receptor mutations in histologically heterogeneous hyperfunctioning nodules of multinodular goiter. Thyroid 1998, 8: 559–564.

    Article  CAS  PubMed  Google Scholar 

  22. Russo D., Tumino S., Arturi F., Vigneri P., Grasso P., Pontecorvi A., Filetti S., Belfiore A. Detection of an activating mutation of the thyrotropin receptor in a case of an autonomously hyperfunctioning thyroid insular carcinoma. J. Clin. Endocrinol. Metab. 1997, 82: 735–738.

    CAS  PubMed  Google Scholar 

  23. Russo D., Arturi F., Schlumberger M., Caillou B., Monier R., Filetti S., Suarez H.G. Activating mutations of the TSH receptor in differentiated thyroid carcinomas. Oncogene 1995, 11: 1907–1911.

    CAS  PubMed  Google Scholar 

  24. Ledent C., Dumont J.E., Vassart G., Parmentier M. Thyroid expression of an A2 adenosine receptor transgene induces thyroid hyperplasia and hyperthyroidism. EMBO J. 1992, 11: 537–542.

    CAS  PubMed Central  PubMed  Google Scholar 

  25. Coppee F., Gerard A., Denef J.F. Early occurrence of metastatic differentiated thyroid carcinomas in transgenic mice expressing the A2α adenosine receptor gene and the human papillomavirus type 16 E7 oncogene. Oncogene 1996, 13: 1471–1482.

    CAS  PubMed  Google Scholar 

  26. Studer H., Peter H.J., Gerber H. Natural heterogeneity of thyroid cells: the basis for understanding thyroid function and nodular goiter growth. Endocr. Rev. 1989, 10: 125–135.

    Article  CAS  PubMed  Google Scholar 

  27. Derwahl M., Manole D., Sobke A., Broecker M. Pathogenesis of toxic thyroid adenomas and nodules: relevance of activating mutations in the TSH-receptor and Gs-α gene, the possible role of iodine deficiency and secondary and TSH-independent molecular mechanisms. Exp. Clin. Endocrinol. Diabetes 1998, 106 (Suppl. 4): S6–S9.

    Article  CAS  PubMed  Google Scholar 

  28. Valeix P., Zarebska M., Preziosi P., Galan P., Pelletier B., Hercberg S. Iodine deficiency in France. Lancet 1999, 353: 1766–1767.

    Article  CAS  PubMed  Google Scholar 

  29. Krohn K., Führer D., Holzapfel H.P., Paschke R. Clonal origin of toxic thyroid nodules with constitutively activating thyrotropin receptor mutations. J. Clin. Endocrinol. Metab. 1998, 83: 130–134.

    CAS  PubMed  Google Scholar 

  30. Kopp P., Kimura E.T., Aeschimann S., Oestreicher M., Tobler A., Fey M.F., Studer H. Polyclonal and monoclonal thyroid nodules coexist within human multinodular goiters. J. Clin. Endocrinol. Metab. 1994, 79: 134–139.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Endocrinology, CHU, Hôpital Sud, France

    Christele Derrien, E. Sonnet, J.-Y. Poirier & D. Maugendre

  2. Department of Molecular Biology and UPR41 CNRS, Faculté de Médecine-Rennes, Rennes, France

    I. Gicquel, J.-Y. Le Gall & V. David

Authors
  1. Christele Derrien
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E. Sonnet
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. I. Gicquel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J.-Y. Le Gall
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J.-Y. Poirier
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. V. David
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. D. Maugendre
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christele Derrien.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Derrien, C., Sonnet, E., Gicquel, I. et al. Non-hyperfunctioning nodules from multinodular goiters: A minor role in pathogenesis for somatic activating mutations in the TSH-receptor and Gsα subunit genes. J Endocrinol Invest 24, 321–325 (2001). https://doi.org/10.1007/BF03343868

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03343868

Key-words

Search

Navigation