Skip to main content
SpringerLink
Log in

Diagnosi genetica del carcinoma midollare della tiroide: implicazioni diagnostiche e terapeutiche

  • Published:
L’Endocrinologo Aims and scope

Riassunto

Il carcinoma midollare della tiroide (CMT) origina dalle cellule C parafollicolari e rappresenta circa il 5–10% di tutti i tumori tiroidei. Può presentarsi in forma sporadica (80%) o in forma familiare (20%), ed in questo caso la trasmissione ereditaria è tipicamente autosomica dominante. La forma ereditaria o familiare si distingue in tre sindromi a seconda che sia caratterizzata dalla sola malattia tiroidea (FCMT o carcinoma midollare familiare isolato) oppure sia associata ad altre neoplasie endocrine, nell’ambito delle neoplasie endocrine multiple di tipo 2 (MEN 2). Mutazioni germinali del gene RET sono coinvolte nella patogenesi della forma familiare e possono essere rivelate mediante analisi molecolare del DNA estratto dai linfociti dei soggetti affetti. L’identificazione della mutazione tipica della famiglia permette di sottoporre ad analisi genetica anche i familiari di primo grado per individuare precocemente i soggetti portatori della mutazione stessa e quindi a rischio di sviluppare la sindrome MEN. Lo screening genetico delle mutazioni di RET deve essere eseguito anche nei soggetti con CMT apparentemente sporadico in quanto una discreta percentuale di questi casi (4–10%) risulta dopo analisi genetica di tipo familiare. Si tratta per lo più di forme familiari misconosciute o de novo, che senza l’analisi di RET non sarebbero state classificate come ereditarie. La ricerca delle mutazioni di RET nel CMT rappresenta oggi il mezzo diagnostico più sensibile e specifico per la diagnosi delle forme familiari di CMT, consentendone il trattamento precoce e/o profilattico e favorendone quindi la prognosi.

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

Bibliografia

  1. Utiger RD. Medullary thyroid carcinoma, genes and the prevention of cancer. N Engl J Med 331: 870, 1994.

    Article  CAS  PubMed  Google Scholar 

  2. Gagel RF, Levy ML, Donovan DT, Alford BR, Whuler T, Tschen JA. Multiple endocrine neoplasia type 2A associated with cutaneus lichen amyloidosis. Ann Intern Med 111: 1537, 1989.

    Article  Google Scholar 

  3. Gimm O, Ukkat J, Dralle H. Determinative factors of biochemical cure after primary and reoperative surgery for sporadic medullary thyroid carcinoma. World J Surg 22: 562, 1998

    Article  CAS  PubMed  Google Scholar 

  4. Elisei R, Bottici V, Luchetti F, Di Coscio G, Romei C, Grasso L, Miccoli P, Iacconi P, Basolo F, Pinchera A, Pacini F. Impact of routine measurement of serum calcitonin on the diagnosis and outcome of medullary thyroid cancer: experience in 10,864 patients with nodular thyroid disorders. J Clin Endocrinol Metab 89: 163, 2004.

    Article  CAS  PubMed  Google Scholar 

  5. Pacini F, Romei C, Miccoli P, Elisei R, Molinaro E, Mancusi F, Iacconi P, Basolo F, Martino E, Pinchera A. Early treatment of hereditary medullary thyroid carcinoma after attribution of multiple endocrine neoplasia type 2 gene mutations. Surgery 118: 1031, 1995.

    Article  CAS  PubMed  Google Scholar 

  6. Mulligan LM, Kwok JB, Healy CS, Eldson MJ, Eng C, Gardner E, Love DR, Mole SE, Moore JK, Papi L, Ponder MA, Telenius H, Tunnacliffe A, Ponder BAJ. Germ-line mutation of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 363: 458, 1993.

    Article  CAS  PubMed  Google Scholar 

  7. Pasini B, Hofstra RMW, Yin L, Bocciardi R, Santamaria G, Grootscholten PM, Ceccherini I, Patrone G, Priolo M, Buys CHCM, Romeo G. The physical map of the human RET proto-oncogene. Oncogene 11: 1737, 1995.

    CAS  PubMed  Google Scholar 

  8. Takahashi M, Buma Y, Iwamoto T, Inaguma Y, Ikeda H, Hiai H. Cloning and expression of the RET proto-oncogene encoding a tyrosine kinase with two potential transmembrane domains. Oncogene 3: 571, 1988.

    CAS  PubMed  Google Scholar 

  9. Santoro M, Carlomagno F, Melillo RM, Billaud M, Vecchio G, Fusco A. Molecular mechanisms of RET activation in human neoplasia. J Endocrinol Invest 22: 811, 1999.

    Article  CAS  PubMed  Google Scholar 

  10. Nakamura T, Ishizaka Y, Nagao M, Hara M, Ishikawa T. Expression of the RET proto-oncogene product in human normal and neoplastic tissues of neural crest origin. J Pathol 172: 255, 1994.

    Article  CAS  PubMed  Google Scholar 

  11. Martucciello G, Ceccherini I, Lerone M, Jassoni V. Pathogenesis of Hirshprung disease. J Pediatr Surg 35: 1017, 2000.

    Article  CAS  PubMed  Google Scholar 

  12. Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote GM, Gagel RF, Van Amstel HKP, Lips CJM, Nishisho I, Takai S., Marsh DJ, Robinson BG., Frank-Raue K, Raue F, Xue F, Romei C, Pacini F, Fink M, Niederle B, Zedenius J, Nordenskjold M, Komminoth P, Hendy GN, Gharib H, Thibodeau SN, Lacroix A, Frilling A, Ponder BAJ, Mulligan LM. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. JAMA 276: 1575, 1996.

    Article  CAS  PubMed  Google Scholar 

  13. Hofstra RMW, Landsvater RM, Ceccherini I, Stulp RP, Stelwagen T, Luo Y, Pasini B, Hoppener JW, Van Amstel AK, Romeo G. Mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and medullary thyroid carcinoma. Nature 367: 375, 1994.

    Article  CAS  PubMed  Google Scholar 

  14. Smith DP, Hougton C, Ponder BAJ. Germline mutation of RET codon 883 in two cases of de novo MEN 2B. Oncogene 15: 1213, 1997.

    Article  CAS  PubMed  Google Scholar 

  15. Niccoli-Sire P, Murat A, Rohmer V, Franc S, Chabrier G, Baldet L, Maes B, Savagner F, Giraud S, Bezieaud S, Kottler ML, Morange S, Conte-Devolx B. Familial medullary thyroid carcinoma with non cysteine Ret mutation: phenotype-genotype relationship in a large series of patients. J Clin Endocrinol Metab 12: 361, 2001.

    Google Scholar 

  16. Pacini F, Elisei R, Romei C, Pinchera A. RET proto-oncogene mutations in thyroid carcinomas: clinical relevance. J Endocrinol Invest 23: 328, 2000.

    Article  CAS  PubMed  Google Scholar 

  17. Jimenez C, Dang GT, Schultz PN, El-Naggar A, Shapiro S, Barnes EA, Evans DB, Vassilopoulou-Sellin R, Gagel RF, Cote GJ, Hoff AO. A novel point mutation of the RET protooncogene involving the second intracellular tyrosine kinase domain in a family with medullary thyroid carcinoma J Clin Endocrinol Metab 89: 3521, 2004.

    Article  CAS  PubMed  Google Scholar 

  18. Gimm O, Neuberg DS, Marsh DJ, Dahia PL, Hoang-Vu C, Raue F, Hinze R, Dralle H, Eng C. Over-representation of a germline RET sequence variant in patients with sporadic medullary thyroid carcinoma and somatic RET codon 918 mutation. Oncogene 18: 1369, 1999.

    Article  CAS  PubMed  Google Scholar 

  19. Elisei R, Cosci B, Romei C, Bottici V, Sculli M, Lari R, Barale R, Pacini F, Pinchera A. RET exon 11 (G691S) polymorphism is significantly more frequent in sporadic medullary thyroid carcinoma than in the general population. J Clin Endocrinol Metab 89: 3579, 2004.

    Article  CAS  PubMed  Google Scholar 

  20. Romei C, Elisei R, Pinchera A, Ceccherini I, Molinaro E, Mancusi F, Martino E, Romeo G, Pacini F. Somatic mutations of the RET proto-oncogene in sporadic medullary thyroid carcinoma are not restricted to exon 16 and are associated with tumo recurrence. J Clin Endocrinol Metab 81: 1619, 1996.

    CAS  PubMed  Google Scholar 

  21. Zedenius J, Larsson C, Brgholm U, Bovee J, Svensson A, Walling G. Mutations of codon 918 in the RET proto-oncogene correlate poor prognosis in sporadic medullary thyroid carcinomas. J Clin Endocrinol Metab 80: 3088, 1995.

    CAS  PubMed  Google Scholar 

  22. Gimm O, Dziema H, Brown J, Hoang-Vu C, Hinze R, Dralle H, Mulligan LM, Eng C. Over-representation of a germline variant in the gene encoding RET co-receptor GFRalpha-1 but not GFRalpha-2 or GFRalpha-3 in cases with sporadic medullary thyroid carcinoma. Oncogene 19: 2161, 2001.

    Article  Google Scholar 

  23. Wiench M, Wygoda Z, Gubala E, Wloch J, Lisowska K, Krassowski J, Scieglinska D, Fiszer-Kierzkowska A, Lange D, Kula D, Zeman M, Roskosz J, Kukulska A, Krawczyk Z, Jarzab B. Estimation of risk of inherited medullary thyroid carcinoma in apparent sporadic patients. J Clin Oncol 19: 1347, 2001.

    Google Scholar 

  24. Brandi ML, Gagel RF, Angeli A, Bilezikian JP, Beck-Peccoz P, Bordi C, Conte-Devolx B, Falchetti A, Gheri RG, Libroia A, Lips CJ, Lombardi G, Mannelli M, Pacini F, Ponder BA, Raue F, Skogseid B, Tamburrano G, Thakker RV, Thompson NW, Tomassetti P, Tonelli F, Wells SA Jr, Marx SJ. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 86: 5658, 2001.

    Article  CAS  PubMed  Google Scholar 

  25. Pacini F, Fontanelli M, Fugazzola L, Elisei R, Romei C, Di Coscio G, Miccoli P, Pinchera A. Routine measurement of serum calcitonin in nodular thyroid diseases allows the preoperative diagnosis of unsuspected sporadic medullary thyroid carcinoma. J Clin Endocrinol Metab 78: 826, 1994.

    CAS  PubMed  Google Scholar 

  26. Ceccherini I, Pasini B, Pacini F, Gullo M, Bongarzone I, Romei C, Santamaria G, Matera I, Mondellini P, Scopsi L, Pinchera A, Pierotti MA, Romeo G. Somatic in frame deletions not involving juxtamembranous cysteine residues strongly activate the RET proto-oncogene. Oncogene 14: 2609, 1997.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Dipartimento di Endocrinologia e Metabolismo, Ortopedia e Traumatologia, Medicina del Lavoro, Sezione di Endocrinologia, Università di Pisa, Pisa, Italia

    Rossella Elisei, Cristina Romei, Barbara Cosci, Furio Pacini & Aldo Pinchera

Authors
  1. Rossella Elisei
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cristina Romei
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Barbara Cosci
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Furio Pacini
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Aldo Pinchera
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rossella Elisei.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Elisei, R., Romei, C., Cosci, B. et al. Diagnosi genetica del carcinoma midollare della tiroide: implicazioni diagnostiche e terapeutiche. L’Endocrinologo 5, 39–46 (2004). https://doi.org/10.1007/BF03344488

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03344488

Search

Navigation