Novel Ret Mutations in Macedonian Patients with Medullary Thyroid Carcinoma: Genotype-Phenotype Correlations/ Нови Ret-Мутации Кај Македонски Пациенти Со Медуларен Карцином На Тироидната Жлезда: Генотипско-Фенотипски Корелации

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Abstract

Medullary thyroid carcinomas (MTCs) are rare neoplasms comprising 2-10% of all thyroid malignnancies. More than 75% are sporadic tumors and the remainder is familial and MEN2 related. Both sporadic and syndromic MTCs frequently show mutations in the RET proto-oncogene. It has been noted that some MTC cases present an indolent, and some an aggressive clinical course. Ki-67 expression is generally low, with documented exceptions, whereas high expression of Bcl-2 has been reported in majority of the cases. Some studies have shown that Ki-67 and Bcl-2 expressions have prognostic value, as well as RET mutational status. We analyzed 20 unrelated MTC cases for Ki-67, Bcl-2 expression and RET mutations and tested their intercorrelations, correlations to the morphologic features and stage of the tumors, as well as their influence on survival. In 13 of the 20 analyzed cases we found 23 sequence changes distributed in exons 8, 10-13 and 16. There were 11 different missense mutations, single nucleotide deletion with frameshift, and 8 different synonymous mutations. Only 4 of the sequence changes have been previously published. Twelve patients (60%) had tumors expressing one or more missense mutations or single nucleotide deletion and 7 of them (35%) had at least one damaging or possibly damaging RET mutation. Most of the tumors had low Ki-67 expression (mean 6.48% of cells) and high Bcl-2 expression (mean 68.3%). Significantly better survival was observed in cases with low Ki-67 (< 6.5%; p < 0.05), high Bcl-2 expression (> 68.3%; p < 0.01) and younger age at diagnosis (< 51 years; p < 0.05).

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  • 1. Jandrichova S Vcelak J Vlcek P Neradilova M Nemec J Bendlova B. Screening of six risk exons of the ret proto-oncogene in families with medullary thyroid carcinoma in the Czech Republic. Journal of Endocrinology. 2004; 183: 257-265.

  • 2. National Cancer Institute. MedullaryThyroid Cancer. available at: http://www.cancer.gov/cancertopics/pdq/genetics/medullarythyroid/HealthProfessional/page2/print

  • 3. Eng Charis. Ret proto-oncogene in the development of human cancer. J Clin Oncol. 1999; 17(1): 380-393.

  • 4. Maitra A Abbas A. K. The endocrine system. In: Robbins and Cotran Pathologic basis of Disease. 7th edition Philadelphia (Pennsylvania): Elsevier Saunders; 2005. 1155-1226.

  • 5. Eng C Clayton D Schuffenecker I Lenoir G Cote G Gangel R. F 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.

  • 6. Matias-Guiu X DeLellis R Moley J. F Gagel R. F Slbores-Saavedra J Bussolati G. et al. Medullary thyroid carcinoma. In: Pathology and genetics of tumors of endocrine system. World Health Organization Classification of Tumors IARC Lyon: IARC Press. 2001; 86-91.

  • 7. Cobanoglu B Ozercan M.R. Staining characteristics of BCL-2 BAX p53 p21 Ki-67 andC-erbB2 in thyroid carcinomas. Erciyes Medical Journal 2007; 29 (3): 201-209.

  • 8. Viale G Roncalli M Grimelius L Graziani D Wilander E Johansson H et al.: Prognostic value of bcl-2 immunoreactivity in medullary thyroid carcinoma. Hum Pathol. 1995; 26(9): 945-50.

  • 9. Gerasimovski D. Census of population households and dwellings in the Republic of Macedonia 2002 Final data. Republic of Macedonia State Statistical Office. Book X. 2002; 10: 18-197.

  • 10. Mograbi B Bocciardi R Bourget I Juhel T Farahi- Far D Romeo G et al. The sensitivity of activated Cys Ret mutants to glial cell line-derived neuritrophic factor is mandatory to rescue neuroectodermal cells from apoptosis. Mol Cell Biol. 2001; 21(20): 6719-6730.

  • 11. Komminoth P. The role of ret proto-oncogene mutation analysis in the diagnosis of multiple endocrine neoplasia type 2 (MEN2) gene carriers and the discrimination of sporadic and familial medullary thyroid carcinomas and pheochromocytomas. Verh Dtsch Ges Pathol. 1995; 79: 50-55.

  • 12. Quayle F. J Fialkowski E. A Benveniste R Moley J. F. Pheochromocytoma penetrance varies by Ret mutation in MEN2A. Surgery. 2007; 142(6): 800-805.

  • 13. Shirahama S Ogura K Takami H Ito K Tohsen T Myiauchi A et al. Mutational analysis of the ret proto-oncogene in 71 Japanese patients with medullary thyroid carcinoma. J Hum Genet.1998; 43(2): 101-106.

  • 14. Linwah Y Cote G.. J Shapiro S. E Ayers G. D Herzog C. E Sellin R. V et al. Multiple endocrine neoplasia type 2. Evaluation of genotype-phenotype relationship. Arch Surg. 2003; 138: 409-416.

  • 15. Arighi E Popsueva A Degl’Innocenti D Borrello M. G Carniti C Perala N. M et al. Biological effects of dual phenotypic Janus mutation of ret cosegregating with both multiple endocrine neoplasia type 2 and Hirschprung’s disease. Mol Endocrinol. 2004; 18(4): 1004-1017.

  • 16. Skinner M. A Safford S. D Reeves J. G Jackson M. E Freemerman A. J. Renal aplasia in humans is associated with Ret mutations. Am J Hum Genet. 2008; 82(2): 344-51.

  • 17. Sanjay J Encinas M Johnson E. M Jr Milbrandt J. Critical and distinct roles for key Ret tyrosine docking sites in renal development. Genes & Development. 2006; 20: 321-333.

  • 18. Yu O. H Murawski I. J Myburgh D. B Gupta I. R. Overexpression of Ret leads to vesicoureteric reflux in mice. Am J Physiol Renal Physiol. 2004; 287: 1123-1130.

  • 19. Yang Y Houle A-M Letendre J Richter A. Ret Gly691Ser mutation is associated with primary vesicoureteral reflux in the French-Canadian population from Quebec. Human Mutation. 2008; 29(5): 695-702.

  • 20. Ensembl. Human gene view. available at: http://www.ensembl.org/Homo_sapiens/geneview?gene=OTTHUMG00000018024;db=vega

  • 21. Gene Cards. RET gene card. available at: http://www.genecards.org/cgi-bin/carddisp.pl?gene=RET

  • 22. Berndt I Reuter M Saller B Frank-Raue K Groth P Grusendorf M et al. A new hot spot for mutations in the ret proto-oncogene causing familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2A. J Clin Endocrinol Metab. 1998; 83(3): 770-774.

  • 23. Bolino A Schuffenecker I Luo Y Seri M Silengo M Tocco T et al. Ret mutations in exons 13 and 14 of FMTC patients. Oncogene. 1995; 10: 2415-2419.

  • 24. Eng C Mulligan L. M Smith D. P Healey C. S Frilling A Raue F et al. Mutation of the ret protooncogene in sporadic medullary thyroid carcinoma. Genes Chromosomes and Cancer. 1995; 12: 209-212.

  • 25. Fattoruso O Quadro L Libroia A Verga U Lupoli G Cascone E et al. A GTG to ATG novel point mutation at codon 804 in exon 14 of the ret protooncogene in two families affected by familial medullary thyroid carcinoma. Human Mutation. 1998; 1: 167-171.

  • 26. Da Silva A. M Maciel R. M Da Silva M. R Toledo S. R De Carvalho M. B Cerutti J. M. A novel germline point mutation in ret exon 8 (Gly533Cys) in large kindred with familial medullary thyroid carcinoma. J Clin Endocrinol Metab. 2003; 88: 5438-5443.

  • 27. Elisei R Cosci B Romei C Bottici V Renzini G Molinaro E et al. Prognostic significance of somatic RET oncogene mutations in sporadic medullary thyroid cancer: a 10-year follow-up study. J Clin Endocrinol Metab. 2008; 93(3): 682-687.

  • 28. Eng C Smith D. P Mulligan L. M Nagai M. A Healey C. S Ponder M. A et al. Point mutation within the thyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumors. Hum Mol Genet. 2003; 3(2): 237-241.

  • 29. Hofstra R. M Landsvater R. M Ceccherini I Stulp R. P Stelwagen T Luo Y et al. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature. 1994; 367(6461): 375-376.

  • 30. Elisei R Romei C Cosci B Agate L Bottici V Molinaro E et al. RET genetic screening in patients with medullary thyroid cancer and their relatives: experience with 807 individuals at one center. J Clin endocrinol Metab. 2007; 92(12): 4725-9.

  • 31. Romei C Elisei R Pinchera A Ceccherini I Molinaro E Mancusi F et al. Somatic mutations of the ret protooncogene in sporadic medullary thyroid carcinoma are not restricted to exon 16 and are associated with tumor recurrence. J Clin Endocrinol Metab. 1996; 81(4): 1619-22.

  • 32. Zedenius J Wallin G Hamberger B Nordenskjold M Weber G Larsson C. Hum mol Genet. 1994; 3(8): 1259-62.

  • 33. Eng C Mulligan L. M Smith D. P Healey C. S Frilling A Raue F et al. Low frequency of germline mutations in the RET proto-oncogene in patients with apparently sporadic medullary thyroid carcinoma.Clin Endocrinol (Oxf). 1995; 43(1): 123-7.

  • 34. Blaugrund J. E Johns M. M Jr Eby Y. J Ball D. W Baylin S. B Hruban R. H Sidransky D. Hum Mol Genet. 1994; 3(10): 1895-7.

  • 35. Machens A Dralle H. Genotype-phenotype based surgical concept of hereditary medullary thyroid carcinoma. World J Surg. 2007; 31(5): 957-68.

  • 36. Frank-Raue K Machens A Scheuba C Niederle B Dralle H Raue F the German MEN2 Study Group. Difference in development of medullary thyroid carcinoma among carriers of RET mutations in codons 790 and 791. Clin endocrinol (Oxf). 2008; Epub ahead of print. PMID 18248648.

  • 37. Elisei R Cosici B Romei C Agate L Piampiani P Miccoli P et al. Identification of novel point mutation in the RET gene (Ala883Thr) which is associated with medullary thyroid carcinoma phenotype only in homozygous condition. J Clin Endocrinol Metab. 2004; 89(11): 5823-7.

  • 38. Orita M Iwahana H Kanazawa H Hayashi K Sekiya T. Detection of polymorphism of human DNA by gel electrophoresis as single-strand conformation polymorphisms. Proc. Natl. Acad. Sci. USA. 1989; 86: 2766-2770.

  • 39. Glavac D Dean M. Optimization of the singlestrand conformation polymorphism (SSCP) technique for detection of point mutations. Hum Mutat. 1993; 2(5): 404-414.

  • 40. Kumar P Henikoff S Ng P. C. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc. 2009; 4(7): 1073-1081.

  • 41. Choi Y Sims G. E Murphy S Miller J. R Chan A. P (2012) Predicting the Functional Effect of Amino Acid Substitutions and Indels. PLoS ONE 7(10): e46688. Available at: http://provean.jcvi.org/index.php

  • 42. StatSoft Inc. (2001). STATISTICA (data analysis software system) version 6. www.statsoft.com.

  • 43. Desmet F. O Hamroun D Lalande M Collod-Beroud G Claustres M Beroud C. Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acid Research 2009. available at: http://www.umd.be/HSF/

  • 44. Schilling T Burck J Sinn H. P Clemens A Otto H. F Hoppner W et al. Prognostic value of codon 918(ATG>ACG) RET proto-oncogene mutations in sporadic medullary thyroid carcinoma. Int J Cancer. 2001; 95(1): 62-6.

  • 45. Leboulleux S Baudin E Travagli J. P Schlumberger M. Medullary thyroid carcinoma. Clinical Endocrinology. 2004; 61: 299-310. doi: 10.1111/j.1365-2265.2004.02037.x

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