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Ret-proto-oncogene analysis in medullary thyroid carcinoma

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Abstract

Introduction: Medullary carcinoma of the thyroid (MTC) is a rare tumour which occurs in both sporadic and hereditary forms. Mutations of the RET proto-oncogene have been identified in hereditary forms. The aim of our study was to confirm or exclude familial disease by examining for germline mutations in the RET proto-oncogene in patients with medullary thyroid carcinoma.

Methods: Nine patients with medullary thyroid carcinoma and 4 of their children were studied. Peripheral blood was used to examine for mutations in the RET proto-oncogene. When this was not available, archival thyroid tissue was used.

Results: Seven patients had clinically sporadic tumours, confirmed by mutational analysis of RET. Four children were at risk of being carriers of a mutated gene, as their fathers had histologically proven MTC and had tested positive for the mutation at codon 618 on exon 10 of the RET proto-oncogene. Three of these children carried the 618 mutation. To date, 2 have had a prophylactic thyroidectomy, the pathology of which revealed C-cell hyperplasia. One child had familial disease excluded by mutational analysis. One patient had a clinical diagnosis of MEN2B confirmed by detection of the 918 mutation on exon 16 of the RET proto-oncogene.

Conclusions: RET proto-oncogene analysis is a reliable method of differentiating familial from sporadic MTC. Mutational information determines which family members of affected kindreds are at risk of developing the disease and can be used to affect clinical management.

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References

  1. Ledger, G. A., Khosla, S., Lindor, N. M., Thibodeau, S. N., Gharib, H. Genetic testing in the diagnosis and management of Multiple Endocrine Neoplasia type 2. Ann. Intern. Med. 1995; 122: 118–124.

    PubMed  CAS  Google Scholar 

  2. Ponder, B. A. J., Finer, N., Coffey, R., Harmer, C. L., Maisey, M., Ormerod, M. G., Pembrey, M. E., Ponder, M. A., Rosswick, P., Shalet, S. & CRC Medullary Thyroid Group. Family screening in medullary thyroid carcinoma presenting without a family history. Quarterly Journal of Medicine 1988; 67: 299–308.

    PubMed  CAS  Google Scholar 

  3. Saad, R. K., Ordonez, N. G., Rashid, R. K., Guido, J. J., Hill, C. S., Hickey, R. C., Samaan, N. A. Medullary carcinoma of the thyroid. A study of the clinical features and prognostic factors in 161 patients. Medicine 1984; 63: 319–342.

    Article  PubMed  CAS  Google Scholar 

  4. Schmike, R. N. Genetic aspects of multiple endocrine neoplasia. Ann. Rev. Med. 1984; 35: 25–31.

    Article  Google Scholar 

  5. Graze, K. G., Spiler, I. J., Tashjian, A. H., Melvin, K. E. W., Cerviskinner, S., Gage, R. F., Miller, H. H., Wolfe, H. J. J. , DeLellis, R. A., Leape, L., Feldman, Z. T., Reichlin, S. Natural history of familial medullary thyroid carcinoma: effect of a programme for early diagnosis. N. Engl. J. Med. 1978; 299:980–985.

    PubMed  CAS  Google Scholar 

  6. Sizemore, G. W., Carney, J. A., Heath, H. Epidemiology of medullary carcinoma of the thyroid gland: a 5 year experience (1971–1976). Surg. Clin. Nth. Am. 1977; 57: 633–645.

    CAS  Google Scholar 

  7. Mulligan, L. M.; Kwok, L. B. J.; Healy, C. S. et al. Germline mutations of the RET proto-oncogene in Multiple Endocrine Neoplasia type 2A. Nature 1993; 363: 458–60.

    Article  PubMed  CAS  Google Scholar 

  8. Santoro, M., Rosato, R., Grieco, M., Berlingieri, M. T., D’amato, G. L., De Franciscis, V., Fusco, A. The RET proto-oncogene is consistently expressed in human phaeochromocytoma and thyroid medullary carcinomas. Oncogene 1990; 5: 1595–1598.

    PubMed  CAS  Google Scholar 

  9. Donis-Keller, H., Dou, S., Chi, D. et al. Mutations in the RET proto-oncogene associated with MEN 2A and FMTC. Hum. Mol. Genet. 1993; 2: 851–6.

    Article  PubMed  CAS  Google Scholar 

  10. Eng, C., Smith, D. P., Mulligan, L. M. et al. A novel point mutation in the Tyrosine Kinase domain of the RET proto- oncogene in sporadic MTC and in a family with FMTC. Oncogene 1995; 10: 509–13.

    PubMed  CAS  Google Scholar 

  11. Mulligan, L. M., Eng, C., Healey, C. S., Clayton, D., Kwok, J. B. J., Ponder, M. A., Gardner, E., Frilling, A., Jackson, C. E., Lehnert, H., Neumann, H. P. H., Thibodeau, S. N., Ponder, B. A. J. Specific mutations of the RET proto- oncogene are related to disease phenotype in MEN2A and FMTC. Nature Genetics 1994; 6: 71–74.

    Article  Google Scholar 

  12. Mulligan, L., Marsh, D. Genotype-phenotype correlation in MEN type 2: report of the international ret mutation consortium. J. Int. Medicine 1995; 238: 343–346.

    CAS  Google Scholar 

  13. Schuffenecker, I., Billaud, M., Calender, A., Chaube, B., Ginet, N., Calmettes, C., Modigliani, E., Lenoir, G. M. RET proto-oncogene mutation in French MEN2A and FMTC families. Hum. Mol. Genet. 1994; 3: 1939–1943.

    Article  PubMed  CAS  Google Scholar 

  14. Carlson, K. M., Dou, S., Chi, D., Scavarda, N., Toshima, K., Jackson, C. E., Wells, S. A., Goodfellow, P. J., Donis- Keller, H. Single missense mutation in the tyrosine kinase catalytic domain of the RET proto-oncogene is associated with multiple endocrine neoplasia type 2B. Proc, Natl. Acad. Sci. USA 1994; 91: 1579–1583.

    Article  CAS  Google Scholar 

  15. Eng, C., Smith, D. P., Mulligan, L. M., Nagai, M. A., Healey, C. S., Ponder, M. A. Gardner, E., Scheumann, G. F. W., Jackson, C. E., Tunnacliffe, A., Ponder, B. A. J. Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours. Hum. Mol. Genet. 1994; 3: 237–241.

    Article  PubMed  CAS  Google Scholar 

  16. Hofstra, R. M. W., Landsvater, R. M., Ceccherini, I., Stulp, R. P., Stelwagen, T., Luo, Y., Pasini, B., Hoppener, J. W. M., Ploos, van Amstel, H. K., Romeo, G., Lips, C. J. M., Buys, C. H. C. M. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature 1994; 367: 375–376.

    Article  PubMed  CAS  Google Scholar 

  17. Eng, C., Mulligan, L. M., Smith, D. P.,, Healey, C. S., Frilling, A., Raue, F., Neumann, H., Pfragner, R., Behmel, A., Lorenzo, M. J., Stonehouse, T. J., Ponder, M. A., Ponder, B. A. J. Mutation of the. RET proto-oncogene in sporadic medullary thyroid carcinoma. Genes, Chromosomes and Cancer 1995; 12: 209–212.

    Article  CAS  Google Scholar 

  18. Zedenius, J., Wallin, G., Hamberger, B., Nordenskjold, M., Weber, G., Larrson, C. Somatic and MEN2A de novo mutations identified in the RET proto-oncogene by screening of sporadic MTC’s. Hum. Mol. Genet. 1994; 3: 1259–1262.

    Article  PubMed  CAS  Google Scholar 

  19. Wright, D. K., Manos, M. Sample preparation from paraffin embedded tissues. In PCR protocols. A guide to methods and applications (ed. M. A. Innis, D. H. Gelfand, J. J. Sninsky, T. J.), pp 153-158. Harcourt Brace Jovanovich, San Diego.

  20. Telander, R. L., Zimmerman, D., van Heerden, J. A., Sizemore, G. W. Results of early thyroidectomy for medullary thyroid carcinoma in children with multiple endocrine neoplasia type 2. J. Pediatr. Surg. 1986; 21: 1190–4.

    Article  PubMed  CAS  Google Scholar 

  21. Gagel, R. F., Tashjian, A. H., Cummings, T., Papathanasopoulos, N., Kaplan, M. M., DeLellis, R. A. The clinical outcome of prospective screening for multiple endocrine neoplasia type 2A. An 18 year experience. N. Engl. J. Med. 1988; 318: 478–484.

    PubMed  CAS  Google Scholar 

  22. Cance, W. G., Wells, S. A. Multiple endocrine neoplasia, Type 11a. Curr. Probl. Surg. 1985; 22: 1–56.

    Article  PubMed  CAS  Google Scholar 

  23. Lairmore, T. C., Wells, S. A. Medullary carcinoma of the thyroid: current diagnosis and management. Semin. Surg. Oncol. 1991; 7: 92–9.

    Article  PubMed  CAS  Google Scholar 

  24. Gagel, R. F., Cote, G. J., Martins Bugalho, M. J. G., Boyd, A. E., Cummins, T., Goepfert, H,, Evans, D. B., Cangir, A., Khorana, S., Schultz, P. N. Clinical use of molecular information in the management of multiple endocrine neoplasia type 2A. J. Intern. Med. 1995; 238: 333–341.

    Article  PubMed  CAS  Google Scholar 

  25. Graham, S. M., Genel, M., Touloukian, R. J., Barwick, K. W., Gertner, J. M., Torony C. Provocative testing for occult medullary carcinoma of the thyroid: findings in seven children with multiple endocrine neoplasia type 11a. J. Pediatr. Surg. 1987; 22: 501–3.

    Article  PubMed  CAS  Google Scholar 

  26. Lips, C. J. M., Landsvater, R. M., Hoppener, J. W. M., Geerdink, R. A., Blijham, G., Jansen-Schillhorn van Veen, J. M., van Gils, A. P. G., de Wit, M. J., Zewald, R. A., Berends, M. J. H., Beemer, F. A., Brouwers-Smalbraak, J., Jansen, R. P. M., Ploos van Amstel, H. K., van Vroonhoven, T. J. M., Vroom, T. M. Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2A. N. Engl. J. Med. 1994; 331: 828–835.

    Article  PubMed  CAS  Google Scholar 

  27. Marsh, D. J., McDowall, D. J., Hyland, V. J., Andrew, S. D., Schnitzler, M., Gaskin, E. L., Nevell, D. F., Diamond, T., Delbridge, L., Clifton-Bligh, P. H., Robinson, B. G. The identification of false positive responses to the pentagastrin stimulation test in RET mutation negative members of MEN2A families. Clin. Endo. 1996; 44: 213–220.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Departments of Surgery and Pathology, University College Dublin, Elm Park, Dublin 4

    D. A. O’Keeffe, A. D. K. Hill, E. W. McDermott, N. J. O’Higgins & K. Sheahan

  2. National Centre for Medical Genetics, Our Lady’s Hospital for Sick Children, Crumlin, Dublin 12

    F. Ryan, D. Barton & R. J. Fitzgerald

Authors
  1. D. A. O’Keeffe
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  2. A. D. K. Hill
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  3. E. W. McDermott
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  4. N. J. O’Higgins
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  5. K. Sheahan
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  6. F. Ryan
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  7. D. Barton
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O’Keeffe, D.A., Hill, A.D.K., McDermott, E.W. et al. Ret-proto-oncogene analysis in medullary thyroid carcinoma. Ir. J. Med. Sc. 167, 226–230 (1998). https://doi.org/10.1007/BF02937418

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