Thyroid carcinomas and Hirschsprung’s disease – 10-year experience with molecular genetic testing of the RET proto-oncogene

Česká verzia

Authors: B. Bendlová ¹ ; Š. Dvořáková ¹; E. Václavíková ¹; V. Sýkorová ¹; P. Vlček ²; R. Škába ³
Authors place of work: Endokrinologický ústav, Praha, ředitel doc. MUDr. Vojtěch Hainer, CSc. ¹; Klinika nukleární medicíny a endokrinologie 2. lékařské fakulty UK a FN Motol, Praha, přednosta doc. MUDr. Petr Vlček, CSc. ²; Klinika dětské chirurgie 2. lékařské fakulty UK a FN Motol, Praha, přednosta prof. MUDr. Jiří Šnajdauf, DrSc. ³
Published in the journal: Vnitř Lék 2006; 52(10): 926-934
Category: Review

Summary

Research of the last ten years approved the role of the RET proto–oncogene in the pathogenesis of thyroid cancer such as medullary thyroid carcinoma (MTC) and papillary thyroid carcinoma (PTC), multiple endocrine neoplasia type 2 syndromes (MEN 2) and Hirschsprung’s disease that could be associated with MTC or MEN 2. Thanks to the molecular genetic testing, which enables to detect the gene mutations, the course of the disease could be predicted and the mutation carriers among the at-risk persons could be cured at the very early, clinically asymptomatic stage of the disease. Then the prophylactic total thyreoidectomy is recommended. Recently, the physiological role of the RET proto-oncogene in normal cell proliferation, differentiation and survival has been intensively studied. Thanks to this new knowledge the possibility of the gene therapy at the RET signaling cascade level is supposed in the treatment of these patients in near future.

Key words:
medullary thyroid carcinoma – papillary thyroid carcinoma – Hirschsprung’s disease – molecular genetic testing – RET proto-oncogene – gene therapy

Zdroje

1. Airaksinen MS, Saarma M. The GDNF family: signalling, biological functions and therapeutic value. Nat Rev Neurosci 2002; 3: 383-394.

2. Attie T, Pelet A, Edery P et al. Diversity of RET proto-oncogene mutations in familial and sporadic Hirschsprung disease. Hum Mol Genet 1995; 4: 1381-1386.

3. Barzon L, Bonaguro R, Palu G et al. New perspectives for gene therapy in endocrinology. Eur J Endocrinol 2000; 143: 447-466.

4. Barzon L, Boscaro M, Palu G. Endocrine aspects of cancer gene therapy. Endocr Rev 2004; 25: 1-44.

5. Bender BU, Gutsche M, Glasker S et al. Differential genetic alterations in von Hippel-Lindau syndrome-associated and sporadic pheochromocytomas. J Clin Endocrinol Metab 2000; 85: 4568-4574.

6. Blume-Jensen P, Hunter T. Oncogenic kinase signalling. Nature 2001; 411: 355-365.

7. Borrego S, Ruiz A, Saez ME et al. RET genotypes comprising specific haplotypes of polymorphic variants predispose to isolated Hirschsprung disease. J Med Genet 2000; 37: 572-578.

8. Brandi ML, Gagel RF, Angeli A et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 2001; 86: 5658-5671.

9. Bugalho MJ, Domingues R, Sobrinho L. Molecular diagnosis of multiple endocrine neoplasia Type 2. Expert Rev Mol Diagn 2003; 3: 769-779.

10. Carlomagno F, Santoro M. Identification of RET kinase inhibitors as potential new treatment for sporadic and inherited thyroid cancer. J Chemother 2004; 16(Suppl 4): 49-51.

11. Ciardiello F, Caputo R, Damiano V et al. Antitumor effects of ZD6474, a small molecule vascular endothelial growth factor receptor tyrosine kinase inhibitor, with additional activity against epidermal growth factor receptor tyrosine kinase. Clin Cancer Res 2003; 9: 1546-1556.

12. Cohen MS, Moley JF. Surgical treatment of medullary thyroid carcinoma. J Intern Med 2003; 253: 616-626.

13. Cote GJ, Gagel RF. Lessons learned from the management of a rare genetic cancer. N Engl J Med 2003; 349: 1566-1568.

14. Coulpier M, Anders J, Ibanez CF. Coordinated activation of autophosphorylation sites in the RET receptor tyrosine kinase: importance of tyrosine 1062 for GDNF mediated neuronal differentiation and survival. J Biol Chem 2002; 277: 1991-1999.

15. de Graaff E, Srinivas S, Kilkenny C et al. Differential activities of the RET tyrosine kinase receptor isoforms during mammalian embryogenesis. Genes Dev 2001; 15: 2433-2444.

16. Decker RA, Peacock ML, Watson P. Hirschsprung disease in MEN 2A: increased spectrum of RET exon 10 genotypes and strong genotype-phenotype correlation. Hum Mol Genet 1998; 7: 129-134.

17. Dvorakova S, Dvorakova K, Malikova M et al. A novel Czech kindred with familial medullary thyroid carcinoma and Hirschsprung's disease. J Pediatr Surg 2005; 40(Suppl e): e1-e6.

18. Dvorakova S, Vaclavikova E, Duskova J et al. Exon 5 of the RET proto-oncogene: a newly detected risk exon for familial medullary thyroid carcinoma, a novel germ-line mutation Gly321Arg. J Endocrinol Invest 2005; 28: 905-909.

19. Dvorakova S, Vaclavikova E, Ryska A et al. Double Germline Mutations in the RET Proto-oncogene in MEN 2A and MEN 2B Kindreds. Exp Clin Endocrinol Diabetes 2006; 114: 192-196.

20. Dvorakova S, Vaclavikova E, Sykorova V et al. New multiple somatic mutations in the RET proto-oncogene associated with a sporadic medullary thyroid carcinoma. Thyroid 2006; 16: 311-316.

21. Eng C, Clayton D, Schuffenecker I et al. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA 1996; 276: 1575-1579.

22. Eng C, Mulligan LM. Mutations of the RET proto-oncogene in the multiple endocrine neoplasia type 2 syndromes, related sporadic tumours, and Hirschsprung disease. Hum Mutat 1997; 9: 97-109.

23. Futreal PA, Coin L, Marshall M et al. A census of human cancer genes. Nat Rev Cancer 2004; 4: 177-183.

24. Gschwind A, Fischer OM, Ullrich A. The discovery of receptor tyrosine kinases: targets for cancer therapy. Nat Rev Cancer 2004; 4: 361-370.

25. Huang SC, Torres-Cruz J, Pack SD et al. Amplification and overexpression of mutant RET in multiple endocrine neoplasia type 2-associated medullary thyroid carcinoma. J Clin Endocrinol Metab 2003; 88: 459-463.

26. Ichihara M, Murakumo Y, Takahashi M. RET and neuroendocrine tumors. Cancer Lett 2004; 204: 197-211.

27. Jain S, Watson MA, DeBenedetti MK et al. Expression profiles provide insights into early malignant potential and skeletal abnormalities in multiple endocrine neoplasia type 2B syndrome tumors. Cancer Res 2004; 64: 3907-3913.

28. Jhiang SM. The RET proto-oncogene in human cancers. Oncogene 2000; 19: 5590-5597.

29. Jindrichova S, Kodet R, Krskova L et al. The newly detected mutations in the RET proto-oncogene in exon 16 as a cause of sporadic medullary thyroid carcinoma. J Mol Med 2003; 81: 819-823.

30. Jindrichova S, Vcelak J, Vlcek P et al. Screening of six risk exons of the RET proto-oncogene in families with medullary thyroid carcinoma in the Czech Republic. J Endocrinol 2004; 183: 257-265.

31. Jindrichova S, Vlcek P, Bendlova B. Genetic causes of the thyroid carcinomas. Cas Lek Cesk 2004; 143: 664-668.

32. Kahraman T, de Groot JW, Rouwe C et al. Acceptable age for prophylactic surgery in children with multiple endocrine neoplasia type 2a. Eur J Surg Oncol 2003; 29: 331-335.

33. Kawamoto Y, Takeda K, Okuno Y et al. Identification of RET autophosphorylation sites by mass spectrometry. J Biol Chem 2004; 279: 14213-14224.

34. Kwok JB, Gardner E, Warner JP et al. Structural analysis of the human ret proto-oncogene using exon trapping. Oncogene 1993; 8: 2575-2582.

35. Lips CJ, Hoppener JW, Van Nesselrooij BP et al. Counselling in multiple endocrine neoplasia syndromes: from individual experience to general guidelines. J Intern Med 2005; 257: 69-77.

36. Liu X, Vega QC, Decker RA et al. Oncogenic RET receptors display different autophosphorylation sites and substrate binding specificities. J Biol Chem 1996; 271: 5309-5312.

37. Machens A, Ukkat J, Brauckhoff M et al. Advances in the management of hereditary medullary thyroid cancer. J Intern Med 2005; 257: 50-59.

38. Manie S, Santoro M, Fusco A et al. The RET receptor: function in development and dysfunction in congenital malformation. Trends Genet 2001; 17: 580-589.

39. Manning G, Whyte DB, Martinez R et al. The protein kinase complement of the human genome. Science 2002; 298: 1912-1934.

40. Mizuno T, Iwamoto KS, Kyoizumi S et al. Preferential induction of RET/PTC1 rearrangement by X-ray irradiation. Oncogene 2000; 19: 438-443.

41. Mulligan LM, Eng C, Healey CS et al. Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC. Nat Genet 1994; 6: 70-74.

42. Nikiforova MN, Stringer JR, Blough R et al. Proximity of chromosomal loci that participate in radiation-induced rearrangements in human cells. Science 2000; 290: 138-141.

43. Pachnis V, Mankoo B, Costantini F. Expression of the c-ret proto-oncogene during mouse embryogenesis. Development 1993; 119: 1005-1017.

44. Parisi MA, Kapur RP. Genetics of Hirschsprung disease. Curr Opin Pediatr 2000; 12: 610-617.

45. Romeo G, Ceccherini I, Celli J et al. Association of multiple endocrine neoplasia type 2 and Hirschsprung disease. J Intern Med 1998; 243: 515-520.

46. Salvatore D, Barone MV, Salvatore G et al. Tyrosines 1015 and 1062 are in vivo autophosphorylation sites in ret and ret-derived oncoproteins. J Clin Endocrinol Metab 2000; 85: 3898-3907.

47. Salvatore G, Nagata S, Billaud M et al. Generation and characterization of novel monoclonal antibodies to the Ret receptor tyrosine kinase. Biochem Biophys Res Commun 2002; 294: 813-817.

48. Santoro M, Carlomagno F, Romano A et al. Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science 1995; 267: 381-383.

49. Santoro M, Melillo RM, Carlomagno F et al. Minireview: RET: normal and abnormal functions. Endocrinology 2004; 145: 5448-5451.

50. Schlessinger J, Lemmon MA. SH2 and PTB domains in tyrosine kinase signaling. Sci STKE 2003; 2003: RE12.

51. Schuchardt A, D'Agati V, Larsson-Blomberg L et al. Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret. Nature 1994; 367: 380-383.

52. Shelling A, Schweder, PM, During, MJ. Principles of gene therapy. In: Baxter JD (ed). Genetics in endocrinology. Philadelphia: Lippincott, Williams and Wilkins 2002: 491-520.

53. Sherman SI. Thyroid carcinoma. Lancet 2003; 361: 501-511.

54. Szinnai G, Meier C, Komminoth P et al. Review of multiple endocrine neoplasia type 2A in children: therapeutic results of early thyroidectomy and prognostic value of codon analysis. Pediatrics 2003; 111(Suppl E): E132-E139.

55. Takahashi M, Iwashita T, Santoro M et al. Co-segregation of MEN2 and Hirschsprung's disease: the same mutation of RET with both gain and loss-of-function? Hum Mutat 1999; 13: 331-336.

56. Vitagliano D, Carlomagno F, Motti ML et al. Regulation of p27Kip1 protein levels contributes to mitogenic effects of the RET/PTC kinase in thyroid carcinoma cells. Cancer Res 2004; 64: 3823-3829.

57. Williams D. Cancer after nuclear fallout: lessons from the Chernobyl accident. Nat Rev Cancer 2002; 2: 543-549.

58. Yip L, Cote GJ, Shapiro SE et al. Multiple endocrine neoplasia type 2: evaluation of the genotype-phenotype relationship. Arch Surg 2003; 138: 409-416.