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Presymptomatic genetic screening in families with multiple endocrine neoplasia type 2

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Abstract

Medullary thyroid carcinoma occurs sporadically or as a part of the inherited cancer syndrome multiple endocrine neoplasia (MEN) type 2. The MEN 2 gene has been identified as the RET proto-oncogene on chromosome 10. In MEN 2A, RET mutations are detectable in one of five cysteine codons within exons 10 and 11 and in MEN 2B in codon 918 (exon 16). Direct DNA testing for RET proto-oncogene mutations is the method of first choice in presymptomatic screening of MEN 2 families. Gene carriers should be offered prophylactic thyroidectomy. The process of DNA analysis for RET proto-oncogene mutations is demonstrated in one family with hereditary medullary thyroid carcinoma. RET mutations were detectable in five of the nine family members at risk.

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Abbreviations

MEN :

Multiple endocrine neoplasia

MTC :

Medullary thyroid carcinoma

FMTC :

Familial medullary thyroid carcinoma

PCR :

Polymerase chain reaction

C-cells :

Calcitonin-producing parafollicular cells

References

  1. Davis RW, Thomas M, Cameron J, St. John TP, Scherer S, Padgett RA (1980) Rapid DNA isolations for enzymatic and hybridisation analysis. Methods Enzymol 65:404–411

    Google Scholar 

  2. Donis-Keller H, Dou S, Chi D, Carlson KM, Toshima K, Lairmore TC, Howe JR, Moley JF, Goodfellow P, Wells SA jr (1993) Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet 2:851–856

    Google Scholar 

  3. Eng C, Smith DP, Mulligan LM, Nagai MA, Healey CS, Ponder MA, Gardner E, Scheumann GFW, Jackson CE, Tunnacliffe A, Ponder BAJ (1994) Point mutations within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours. Hum Mol Genet 3:237–241

    Google Scholar 

  4. Frilling A, Röher H-D, Ponder BAJ (1993) Presymptomatic biochemical and genetic screening in multiple endocrine neoplasia type 2A families. Exp Clin Endocrinol 101:92–96

    Google Scholar 

  5. Frilling A, Röher HD, Ponder BAJ, Goretzki P-E, Reiners C (1993) Erfahrungen mit präsymptomatischem Screening bei Patienten mit C-Zell-Carcinom der Schilddrüse. Chirurg 64:28–35

    Google Scholar 

  6. Gagel RF, Tashjian AH jr, Cummings T, Papathanasopoulos N, Kaplan MM, Delellis RA, Wolfe HJ, Reichlin S (1988) The clinical outcome of prospective screening for multiple endocrine neoplasia type 2A, an 18-year experience. New Engl J Med 318:478–484

    Google Scholar 

  7. Gardner E, Papi L, Easton DF, Cummings T, Jackson CE, Kaplan M, Love DR, Mole Se, Moore JK, Mulligan LM, Norum RA, Ponder MA, Reichlin S, Stall G, Telenius H, Telenius-Berg M, Tunnacliffe A, Ponder BAJ (1993) Genetic linkage studies map the multiple endocrine neoplasia type 2 loci to a small interval on chromosome 10q11. 2. Hum Mol Genet 2:241–246

    Google Scholar 

  8. Grieco M, Santoro M, Berlingieri MT, Melillo RM, Donghi R, Bongarzone I, Pierotti MA, Della Porta G, Fusco A, Vecchio G (1990) PTC is a novel rearrangement form of the ret protooncogene and is frequently detected in vivo in human thyroid papillary carcinomas. Cell 60:557–563

    Google Scholar 

  9. Hofstra RMW, Landvater RM, Ceccherini I, Stulp RP, Stelwagen T, Luo Y, Pasini B, Höppener JWM, Ploos van Amstel HK, Romeo G, Lips CJM, Buys CHCM (1994) A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature 367:375–376

    Google Scholar 

  10. Lairmore TC, Howe JR, Korte JA, Dilley WG, Aine L, Aine E, Wells SA Jr, Donis-Keller H (1991) Familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2B map to the same region of chromosome 10 as multiple endocrine neoplasia type 2A. Genomics 9:181–192

    Google Scholar 

  11. Lairmore TC, Dou S, Howe JR, Chi D, Carlson K, Veile R, Mishra SK, Wells SA, Donis-Keller H (1993) A 1,5-megabase yeast artificial chromosome conting from human chromosome 10q11. 2 connecting three genetic loci (RET, D10S94 and D10S102) closely linked to the MEN 2A locus. Proc Natl Acad Sci USA 90:492–496

    Google Scholar 

  12. Lathrop M, Nakamura Y, Cartwright P, O'Connell P, Leppert M, Jones C, Tateishi H, Bragg T, Lalouel J-M, White R (1988) A primary genetic map of markers for human chromosome 10. Genomics 2:157–164

    Google Scholar 

  13. Lips CJM, Landsvater RM, Höppener JWM, Geerdink RA, Blijham G, Jansen-Schillhorn van Veen JM, van Gils A, de Wit M, Zewald RA, Berends MJH, Beemer FA, Brouwers-Smalbraak J, Jansen RPM, Ploos van Amstel HK, van Vroonhoven TJMV, Vroom TM (1994) Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2A. N Engl J Med 331:828–83514. Mathew CGP, Chin KS, Easton DF, Thorpe K, Carter C, Liou GI, Fong S-L, Bridges CDB, Haak H, Nieuwenhuijzen Kruseman AC, Schifter S, Hansen HH, Telenius H, Telenius-Berg M, Ponder BAJ (1987) A linked genetic marker for multiple endocrine neoplasia type 2A on chromosome 10. Nature 328:527–528

    Google Scholar 

  14. Mathew CGP, Easton DF, Nakamura Y, Ponder BAJ and the MEN 2A International Collaborative Group (1991) Presymptomatic screening for multiple endocrine neoplasia type 2A with linked DNA markers. Lancet 337:7–11

    Google Scholar 

  15. Miya A, Yamamoto M, Morimoto H, Tanaka N, Shin E, Karakawa K, Toyoshima K, Ishizaka Y, Mori T, Takai SI (1992) Expression of the ret proto-oncogene in human medullary thyroid carcinomas and pheochromocytomas of MEN 2A. Henry Ford Hosp Med J 40:215–219

    Google Scholar 

  16. Mole SE, Mulligan LM, Healey CS, Ponder BAJ, Tunnacliffe A (1993) Localisation of the gene for multiple endocrine neoplasia type 2A to a 480 kb region in chromosome band 10q11. 2. Hum Mol Genet 2:247–252

    Google Scholar 

  17. Mulligan LM, Kwok JBJ, Healey CS, Elsdon MJ, Eng C, Gardner E, Love DR, Mole SE, Moore JK, Papi L, Ponder MA, Telenius H, Tunnacliffe A, Ponder BAJ (1993) Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 363:458–460

    Google Scholar 

  18. Mulligan LM, Eng C, Healey CS, Clayton D, Kwok JBJ, Gardner E, Ponder MA, Frilling A, Jackson CE, Lehnert H, Neumann HPH, Thibodeau SN, Ponder BAJ (1994) Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC. Nature Genet 6:70–74.

    Google Scholar 

  19. Mulligan LM, Marsh DJ, Robinson BG, Schufferdecker I, Zedenius J, Lips CJM, Gagel RF, Takai S-I, Noll WW, Fink M, Raue F, Lacroix A, Thibodeau S, Frilling A, Ponder BAJ, Eng C (1995) Genotype-phenotype correlation in MEN 2: report of the International RET Mutation Consortium. J Int Med (in press)

  20. Nagao M, Ishizaka Y, Nakagawara A, Kohno K, Kuwano M, Tahira T, Itoh F, Ikeda I, Sugimura T (1990) Expression of ret proto-oncogene in human neuroblastomas. Jpn J Cancer Res 81:309–312

    Google Scholar 

  21. Nakamura Y, Mathew CGP, Sobol H, Easton DF, Telenius H, Gragg T, Chin K, Clark J, Jones C, Lenoir GM, White R, Ponder BAJ (1989) Linked markers flanking the gene for multiple endocrine neoplasia type 2A. Genomics 5:199–203

    Google Scholar 

  22. Norum RA, Lafreniere RG, O'Neal LW, Nikolai TF, Delaney JP, Sisson JC, Sobol H, Lenoir GM, Ponder BAJ, Willard HF, Jackson CE (1990) Linkage of the multiple endocrine neoplasia type 2B gene (MEN 2B) to chromosome 10 markers linked to MEN 2A. Genomics 8:313–317

    Google Scholar 

  23. Ponder BAJ, Coffey R, Gagel RF, Semple P, Ponder MA, Pembrey ME, Telenius-Berg M, Easton DF (1988) Risk estimation and screening in families of patients with medullary thyroid carcinoma. Lancet 1:397–401

    Google Scholar 

  24. Ponder BAJ, Finer N, Coffey R, Harmer CL, Maisey M, Ormerod MG, Pembrey ME, Ponder MA, Rosswick P, Shalet S (1988) Family screening in medullary thyroid carcinoma presenting without a family history. Q J Med 252:299–308

    Google Scholar 

  25. Raue F, Kotzerke J, Reinwein D, Schröder S, Röher HD, Deckart H, Höfer R, Ritter M, Seif F, Buhr H, Beyer J, Schober O, Becker W, Neumann H, Calvi J, Winter J, Vogt H and the German Medullary Thyroid Carcinoma Study Group (1993) Prognostic factors in medullary thyroid carcinoma: evaluation of 741 patients from the German Medullary Thyroid Carcinoma Register. Clin Investig 71:7–12

    Google Scholar 

  26. Santoro M, Rosato R, Grieco M, Berlingieri MT, Luca-Colucci D'Amato G, de Franciscis V, Fusco A (1990) The ret proto-oncogene is consistently expressed in human phaeochromocytoma and thyroid medullary carcinomas. Oncogene 5:1595–1598

    Google Scholar 

  27. Simpson NE, Kidd KK, Goodfellow PJ, McDermid H, Myers S, Kidd JR, Jackson CE, Duncan AMV, Farrer LA, Brasch K, Castiglione C, Genel M, Gertner J, Greenberg CR, Gusella JF, Holden JJA, White BN (1987) Assignment of multiple endocrine neoplasia type 2A to chromosome 10 by linkage. Nature 328:528–530

    Google Scholar 

  28. Simpson WJ, Carruthers JS, Malkin D (1990) Results of a screening program for C-cell disease (medullary thyroid cancer and C-cell hyperplasia). Cancer 65:1570–1576

    Google Scholar 

  29. Sobol H, Narod SA, Nakamura Y, Boneu A, Calmettes C, Chadenas D, Charpentier G, Chatal JF, Delepine N, Delisle MJ, Dupond JL, Gardet P, Godefroy H, Guillausseau P-J, Guillausseau-Scholer C, Houdent C, Lalau JD, Mace G, Parmentier C, Soubrier F, Tourniaire J, Lenoir GM (1989) Screening for multiple endocrine neoplasia type 2A with DNA-polymorphism analysis. N Engl J Med 321:996–1001

    Google Scholar 

  30. Takahashi M, Buma Y, Iwamoto T, Inaguma Y, Ikeda H, Hiroshi H (1988) Cloning and expression of the ret proto-oncogene encoding a thyrosine kinase with two potential transmembrane domains. Oncogene 3:571–578

    Google Scholar 

  31. Wells SA, Chi DD, Toshima K, Dehner LP, Coffin CM, Dowton B, Ivanovich JL, DeBenedetti MK, Dilley WG, Moley JF, Norton JA, Donis-Keller H (1994) Predictive DNA testing and prophylactic thyroidectomy in patients at risk for multiple endocrine neoplasia type 2A. Ann Surg 220:237–250

    Google Scholar 

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Authors and Affiliations

  1. Abteilung für Allgemeinchirurgie, Chirurgische Klinik, Universität Hamburg, Martinistrasse 52, D-20251, Hamburg, Germany

    A. Frilling & C. E. Broelsch

  2. Abteilung Molekulare Diagnostik, Institut für Hormon-und Fortpflanzungsforschung, Universität Hamburg, Martinistrasse 52, D-20251, Hamburg, Germany

    W. Höppner

  3. Cancer Research Campaign, Human Cancer Genetics Research Group, Department of Pathology, Cambridge University, Cambridge, UK

    C. Eng & L. Mulligan

  4. Abteilung Innere Medizin I, Endokrinologie und Stoffwechsel, Universität Heidelberg, Heidelberg, Germany

    F. Raue

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  1. A. Frilling
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  2. W. Höppner
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  3. C. Eng
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  4. L. Mulligan
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Frilling, A., Höppner, W., Eng, C. et al. Presymptomatic genetic screening in families with multiple endocrine neoplasia type 2. J Mol Med 73, 229–233 (1995). https://doi.org/10.1007/BF00189922

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  • DOI: https://doi.org/10.1007/BF00189922

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