Caracterização clínica e molecular de pacientes com carcinoma medular de tireoide do estado da Bahia

Detalhes bibliográficos
Autor(a) principal: Matta, Rafael Reis Campos da
Data de Publicação: 2023
Tipo de documento: Dissertação
Idioma: por
Título da fonte: Repositório Institucional da UFBA
Texto Completo: https://repositorio.ufba.br/handle/ri/36876
Resumo: Introdução: O carcinoma medular de tireoide é um câncer raro que tem origem nas células C e pode se apresentar na forma esporádica (75%) ou hereditária (25%), como componente das síndromes de neoplasia endócrina múltipla tipo 2. Tanto a doença esporádica quanto a doença hereditária têm como principal causa as mutações no proto-oncogene RET. Sua incidência e suas bases moleculares ainda são desconhecidas e pouco investigadas, sobretudo em estados do Nordeste do país. Na Bahia, ainda não há registro de estudos que tenham investigado o comportamento e as características dessa doença na região. Objetivo: Caracterizar clínica e molecularmente pacientes com carcinoma medular de tireoide no estado da Bahia. Metodologia: Estudo transversal e descritivo que envolveu pacientes com diagnóstico histopatológico da doença, encaminhados para realização do teste molecular, no período de 2020 a 2022. Os dados clínicos-patológicos foram coletados a partir dos laudos anatomopatológicos e imuno-histoquímicos dos pacientes. O DNA genômico foi extraído a partir do sangue periférico. Os éxons 10, 11, 13, 14 e 15 do RET foram amplificados por reação em cadeia da polimerase e, posteriormente, sequenciados pelo método de Sanger. Resultados: Incluíram-se 29 pacientes no estudo (82,8% do sexo feminino). A idade média do diagnóstico foi de 46,5 ± 13,1 anos e o tamanho médio do tumor de 2,1 ± 1,4 cm. Invasão capsular, invasão extratireoidiana e invasão angiolinfática ocorreram em 13,8%, 3,4% e 6,9% dos casos, respectivamente. De acordo com a classificação TNM, 38% dos tumores foram estadiados como T1a, 27,6% T1b, 24,1% T2 e 10,3% T3. Metástase linfonodal regional (N1) esteve presente em 44,8% dos casos. A presença de metástase a distância (M1) para o mediastino foi observada em um caso (3,4%). Variantes do proto-oncogene RET foram identificadas em 55,2% dos pacientes. A variante patogênica C634R foi identificada em um paciente (3,4%). Polimorfismos do RET foram identificados em 51,7% dos pacientes, sendo L769L o polimorfismo mais frequente. Discussão: RET C634R está associada ao diagnóstico de neoplasia endócrina múltipla tipo 2A, sendo descrita na literatura como a variante patogênica mais frequente (30-50%) entre os pacientes afetados. Conclusão: Este estudo descreveu, pela primeira vez, o perfil clínico e molecular de pacientes com carcinoma medular de tireoide na Bahia. Uma variante patogênica germinativa do RET foi identificada confirmando o diagnóstico de neoplasia endócrina múltipla tipo 2A em um paciente. Polimorfismos do proto-oncogene RET foram identificados em 51,7% dos pacientes.
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spelling 2023-04-19T12:49:13Z2023-04-19T12:49:13Z2023-02-27MATTA, Rafael Reis Campos da. Caracterização clínica e molecular de pacientes com carcinoma medular de tireoide do estado da Bahia. 84 f. il. Orientador: Helton Estrela Ramos. 2023. Dissertação (Mestrado) – Programa de Pós-Graduação em Processos Interativos dos Órgãos e Sistemas, Instituto de Ciências da Saúde, Universidade Federal da Bahia, Salvador.https://repositorio.ufba.br/handle/ri/36876Introdução: O carcinoma medular de tireoide é um câncer raro que tem origem nas células C e pode se apresentar na forma esporádica (75%) ou hereditária (25%), como componente das síndromes de neoplasia endócrina múltipla tipo 2. Tanto a doença esporádica quanto a doença hereditária têm como principal causa as mutações no proto-oncogene RET. Sua incidência e suas bases moleculares ainda são desconhecidas e pouco investigadas, sobretudo em estados do Nordeste do país. Na Bahia, ainda não há registro de estudos que tenham investigado o comportamento e as características dessa doença na região. Objetivo: Caracterizar clínica e molecularmente pacientes com carcinoma medular de tireoide no estado da Bahia. Metodologia: Estudo transversal e descritivo que envolveu pacientes com diagnóstico histopatológico da doença, encaminhados para realização do teste molecular, no período de 2020 a 2022. Os dados clínicos-patológicos foram coletados a partir dos laudos anatomopatológicos e imuno-histoquímicos dos pacientes. O DNA genômico foi extraído a partir do sangue periférico. Os éxons 10, 11, 13, 14 e 15 do RET foram amplificados por reação em cadeia da polimerase e, posteriormente, sequenciados pelo método de Sanger. Resultados: Incluíram-se 29 pacientes no estudo (82,8% do sexo feminino). A idade média do diagnóstico foi de 46,5 ± 13,1 anos e o tamanho médio do tumor de 2,1 ± 1,4 cm. Invasão capsular, invasão extratireoidiana e invasão angiolinfática ocorreram em 13,8%, 3,4% e 6,9% dos casos, respectivamente. De acordo com a classificação TNM, 38% dos tumores foram estadiados como T1a, 27,6% T1b, 24,1% T2 e 10,3% T3. Metástase linfonodal regional (N1) esteve presente em 44,8% dos casos. A presença de metástase a distância (M1) para o mediastino foi observada em um caso (3,4%). Variantes do proto-oncogene RET foram identificadas em 55,2% dos pacientes. A variante patogênica C634R foi identificada em um paciente (3,4%). Polimorfismos do RET foram identificados em 51,7% dos pacientes, sendo L769L o polimorfismo mais frequente. Discussão: RET C634R está associada ao diagnóstico de neoplasia endócrina múltipla tipo 2A, sendo descrita na literatura como a variante patogênica mais frequente (30-50%) entre os pacientes afetados. Conclusão: Este estudo descreveu, pela primeira vez, o perfil clínico e molecular de pacientes com carcinoma medular de tireoide na Bahia. Uma variante patogênica germinativa do RET foi identificada confirmando o diagnóstico de neoplasia endócrina múltipla tipo 2A em um paciente. Polimorfismos do proto-oncogene RET foram identificados em 51,7% dos pacientes.Introduction: Medullary carcinoma of the thyroid (MCT) is a rare cancer that originates from C cells and may be sporadic (75%) or hereditary (25%) as a component of multiple endocrine neoplasia syndrome. Both sporadic disease and hereditary disease are due to mutations in the RET protooncogene mainly. MCT incidence and its molecular basis is still unknown and little investigated, especially in the northeastern states of the country. In Bahia, there are still no records of studies that have investigated the behavior and characteristics of this disease in the region. Objective: To characterize clinically and molecularly patients with MCT in the state of Bahia. Methodology: Cross-sectional and descriptive study involving patients with histopathological diagnosis of MCT which were submitted to DNA analysis from 2020 to 2022. Clinical pathology data were collected from the patients' anatomopathological and immunohistochemical reports. Genomic DNA was extracted from peripheral blood. Exons 10, 11, 13, 14 and 15 from the RET were amplified by Polymerase Chain Reaction (PCR) and subsequently they were sequenced by the Sanger method. Results: Clinical data: 29 patients were included in the study (82.8% female). The mean age from diagnosis was 46.5 ± 13.1 years and mean tumor size was 2.1 ± 1.4 cm. Capsular, blood vessel and lymphatic invasion and extrathyroidal invasion occurred in 13.8%, 6.9% and 3.4% of cases, respectively. According to the TNM classification, 38% of the tumors were staged as T1a, 27.6% T1b, 24.1% T2 and 10.3% T3. Regional lymph node metastasis (N1) was present in 44.8% of cases. The presence of distant metastasis (M1) to the mediastinum was observed in one case (3.4%). RET protooncogene variants were identified in 55.2% of patients. The pathogenic variant C634R was identified in one patient (3.4%). RET polymorphisms were identified in 51.7% of patients, from which L769L was the most frequent polymorphism. Discussion: RET C634R is associated with the diagnosis of multiple endocrine neoplasia type 2A and it is described in literature of the area as the most frequent pathogenic variant (30-50%) among affected patients. Conclusion: The study described unprecedentedly the clinical and molecular profile of patients with medullary carcinoma of the thyroid in Bahia. A germline pathogenic variant of RET was identified confirming the diagnosis of multiple endocrine neoplasia type 2A in one patient. RET protooncogene polymorphisms were identified in 51.7% of patients.Submitted by Rafael da Matta (rafael.matta@ufba.br) on 2023-04-19T11:06:26Z No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) Dissertação Rafael Reis - Versão final pós revisões.pdf: 1958645 bytes, checksum: 67137c1772bb2e243e92e9631e0c53c3 (MD5)Approved for entry into archive by Delba Rosa (delba@ufba.br) on 2023-04-19T12:49:13Z (GMT) No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) Dissertação Rafael Reis - Versão final pós revisões.pdf: 1958645 bytes, checksum: 67137c1772bb2e243e92e9631e0c53c3 (MD5)Made available in DSpace on 2023-04-19T12:49:13Z (GMT). No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) Dissertação Rafael Reis - Versão final pós revisões.pdf: 1958645 bytes, checksum: 67137c1772bb2e243e92e9631e0c53c3 (MD5) Previous issue date: 2023-02-27Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorporUniversidade Federal da BahiaPrograma de Pós-Graduação em Processos Interativos dos Órgãos e Sistemas (PPGORGSISTEM) UFBABrasilInstituto de Ciências da Saúde - ICSAttribution-NonCommercial-NoDerivs 3.0 Brazilhttp://creativecommons.org/licenses/by-nc-nd/3.0/br/info:eu-repo/semantics/openAccessMedullary carcinomaMutationSingle-nucleotide polymorphismThyroidectomyCNPQ::CIENCIAS BIOLOGICAS::GENETICA::GENETICA HUMANA E MEDICACarcinoma medularMutaçãoPolimorfismo de nucleotídeo únicoTireoidectomiaCaracterização clínica e molecular de pacientes com carcinoma medular de tireoide do estado da BahiaClinical and molecular characterization of patients with medullary carcinoma of the thyroid in the state of BahiaMestrado Acadêmicoinfo:eu-repo/semantics/masterThesisinfo:eu-repo/semantics/publishedVersionRamos, Helton Estrelahttps://orcid.org/0000-0002-2900-2099http://lattes.cnpq.br/5624505454133902Cerqueira, Taíse Lima de Oliveirahttp://lattes.cnpq.br/0365632293236220Ramos, Helton Estrelahttps://orcid.org/0000-0002-2900-2099http://lattes.cnpq.br/5624505454133902Carvalho, Acacia Fernandes Lacerda dehttps://orcid.org/0000-0003-3639-338Xhttp://lattes.cnpq.br/8227096712575197Camacho, Cléber Pintohttps://orcid.org/0000-0002-8653-0031http://lattes.cnpq.br/1832800364435894http://lattes.cnpq.br/1369558540098706Matta, Rafael Reis Campos da1. Deng Y, Li H, Wang M, Li N, Tian T, Wu Y, et al. Global burden of thyroid cancer from 1990 to 2017. JAMA Netw Open. 2020;3(6):e208759. doi: 10.1001/jamanet workopen.2020.8759 2. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-49. doi:10.3322/caac.21660 3. Instituto Nacional de Câncer José Alencar Gomes Da Silva. Estimativa 2020: incidência de câncer no Brasil. Rio de Janeiro: INCA; 2022. Disponível em: https://www.inca.gov.br/estimativa 4. World Health Organization. Classification of tumours. Endocrine tumours. Lyon: International Agency for Research on Cancer; 2022. Disponível em: https://tumourclassification.iarc.who.int/welcome/ 5. Czarniecka A, Oczko-Wojciechowska M, Hajduk A, Zeman M, Jarzab B. Current surgical management in RET mutation carriers. Endokrynol Pol. 2019;70(4):367-79. doi:10.5603/EP.a2019.0021 6. Kawai K, Takahashi M. Intracellular RET signaling pathways activated by GDNF. Cell Tissue Res. 2020;382(1):113-23. doi:10.1007/s00441-020-03262-1 7. Takahashi M, Ritz J, Cooper GM. Activation of a novel human transforming gene, ret, by DNA rearrangement. Cell. 1985;42(2):581-88. doi:10.1016/0092-8674(85)90115-1 8. Raue F, editor. Medullary thyroid carcinoma. Recent results cancer res. Cham: Springer International Publishing; 2015. 204 p. doi.org/10.1007/978-3-319-22542-5 9. Hofstra RM, Landsvater RM, Ceccherini I, Stulp RP, 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):375-6. doi: 10.1038/367375a0. 10. Kebebew E, Ituarte PH, Siperstein AE, Duh QY, Clark OH. Medullary thyroid carcinoma: clinical characteristics, treatment, prognostic factors, and a comparison of staging systems. Cancer. 2000;88(5):1139-48. doi: 10.1002/(sici)1097-0142(20000301)88:5<1139::aid-cncr26>3.0.co;2-z. 11. Romei C, Cosci B, Renzini G, Bottici V, Molinaro E, Agate L, et al. RET genetic screening of sporadic medullary thyroid cancer (MTC) allows the preclinical diagnosis of unsuspected gene carriers and the identification of a relevant percentage of hidden familial MTC (FMTC). Clin Endocrinol (Oxf). 2011;74(2):241-7. doi: 10.1111/j.1365-2265.2010.03900.x 12. Simbolo M, Mian C, Barollo S, Fassan M, Mafficini A, Neves D, et al. High-throughput mutation profiling improves diagnostic stratification of sporadic medullary thyroid carcinomas. Virchows Arch. 2014;465(1):73-8. doi: 10.1007/s00428-014-1589-3. 13. Wei S, LiVolsi VA, Montone KT, Morrissette JJ, Baloch ZW. Detection of Molecular Alterations in Medullary Thyroid Carcinoma Using Next-Generation Sequencing: an Institutional Experience. Endocr Pathol. 2016;27(4):359-362. doi: 10.1007/s12022-016-9446-3. 14. Romei C, Casella F, Tacito A, Bottici V, Valerio L, Viola D, et al. New insights in the molecular signature of advanced medullary thyroid cancer: evidence of a bad outcome of cases with double RET mutations. J Med Genet. 2016;53(11):729-734. doi: 10.1136/jmedgenet-2016-103833. 15. Hedayati M, Zarif Yeganeh M, Sheikholeslami S, Afsari F. Diversity of mutations in the RET proto-oncogene and its oncogenic mechanism in medullary thyroid cancer. Crit Rev Clin Lab Sci. 2016;53(4):217-27. doi: 10.3109/10408363.2015.1129529. 16. Qu N, Shi X, Zhao JJ, Guan H, Zhang TT, Wen SS, et al. Genomic and Transcriptomic Characterization of Sporadic Medullary Thyroid Carcinoma. Thyroid. 2020;30(7):1025-1036. doi: 10.1089/thy.2019.0531. 17. Kouvaraki MA, Shapiro SE, Perrier ND, Cote GJ, Gagel RF, Hoff AO, et al. RET proto-oncogene: a review and update of genotype-phenotype correlations in hereditary medullary thyroid cancer and associated endocrine tumors. Thyroid. 2005;15(6):531-44. doi: 10.1089/thy.2005.15.531. 18. Wells AS Junior, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015;25(6):567-10. doi:10.1089/thy.2014.0335 19. Chen H, Sippel RS, O'Dorisio MS, Vinick AI, Lloyd RV, Pacak K, et al. The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer. Pancreas. 2010;39(6):775-83. doi: 10.1097/ MPA.0b013e3181ebb4f0 20. Maia AL, Siqueira DR, Kulcsar MA, Tincani AJ, Mazeto GM, Maciel LM. Diagnosis, treatment, and follow-up of medullary thyroid carcinoma: recommendations by the Thyroid Department of the Brazilian Society of Endocrinology and Metabolism. Arch Endocrinol Metab. 2014;58(7):667-700. doi:10.1590/0004-2730000003427 21. Viola D, Elisei R. Management of Medullary Thyroid Cancer. Endocrinol Metab Clin North Am. 2019;48(1):285-301. doi:10.1016/j.ecl.2018.11.006 22. Randle RW, Balentine CJ, Leverson GE, Havlena JA, Sippel RS, Schneider DF, et al. Trends in the presentation, treatment, and survival of patients with medullary thyroid cancer over the past 30 years. Surgery. 2017;161(1):137-46. doi:10.1016/ j.surg.2016.04.053 23. Gilliland FD, Hunt WC, Morris DM, Key CR. Prognostic factors for thyroid carcinoma. A population-based study of 15,698 cases from the Surveillance, Epidemiology and End Results (SEER) program 1973-1991. Cancer. 1997;79(3):564-73. doi:10.1002/(sici)1097-0142(19970201)79:3<564::aid-cncr20>3.0.co;2-0 24. Kuo EJ, Sho S, Li N, Zanocco KA, Yeh MW, Livhits MJ. Risk Factors Associated With Reoperation and Disease-Specific Mortality in Patients With Medullary Thyroid Carcinoma. JAMA Surg. 2018;153(1):52-9. doi:10.1001/jamasurg.2017.3555 25. Miranda-Filho A, Lortet-Tieulent J, Bray F, et al. Thyroid cancer incidence trends by histology in 25 countries: a population-based study. Lancet Diabetes Endocrinol. 2021;9(4):225-234. doi:10.1016/S2213-8587(21)00027-9 26. Sierra MS, Soerjomataram I, Forman D. Thyroid cancer burden in Central and South America. Cancer Epidemiol. 2016;44 Suppl 1:S150-S157. doi:10.1016/j.canep.2016.07.017 27. Borges AKDM, Ferreira JD, Koifman S, Koifman RJ. Thyroid cancer in Brazil: a descriptive study of cases held on hospital-based cancer registries, 2000-2016. Epidemiol Serv Saude. 2020;29(4):e2019503. doi:10.5123/s1679-49742020000400012 28. Ceolin L, Duval MADS, Benini AF, Ferreira CV, Maia AL. Medullary thyroid carcinoma beyond surgery: advances, challenges, and perspectives. Endocr Relat Cancer. 2019;26(9):R499-R518. doi:10.1530/ERC-18-0574 29. Ball DW. Medullary thyroid cancer: monitoring and therapy. Endocrinol Metab Clin North Am. 2007;36(3):823-viii. doi:10.1016/j.ecl.2007.04.001 30. Sippel RS, Kunnimalaiyaan M, Chen H. Current management of medullary thyroid cancer. Oncologist. 2008;13(5):539-47. doi:10.1634/theoncologist.2007-0239 31. Roy M, Chen H, Sippel RS. Current understanding and management of medullary thyroid cancer. Oncologist. 2013;18(10):1093-100. doi:10.1634/theoncologist.2013-0053 32. Leboulleux S, Baudin E, Travagli JP, Schlumberger M. Medullary thyroid carcinoma. Clin Endocrinol (Oxf). 2004;61(3):299-310. doi:10.1111/j.1365-2265.2004.02037.x 33. Fussey JM, Vaidya B, Kim D, Clark J, Ellard S, Smith JA. The role of molecular genetics in the clinical management of sporadic medullary thyroid carcinoma: a systematic review. Clin Endocrinol (Oxf). 2019;91(6):697-707. doi:10.1111/cen.14060 34. Wells SA Jr, Pacini F, Robinson BG, Santoro M. Multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma: an update. J Clin Endocrinol Metab. 2013;98(8):3149-64. doi:10.1210/jc.2013-1204 35. Newey PJ. Multiple endocrine neoplasia. Medicine. 2021;49(9):539-43. doi.org/10.1016/j.mpmed.2021.06.003 36. Mathiesen JS, Effraimidis G, Rossing M, Rasmussen AK, Hoejberg L, Bastholt L, et al. Multiple endocrine neoplasia type 2: a review. Semin Cancer Biol. 2022;79:163-79. doi:10.1016/j.semcancer.2021.03.035 37. Raue F, Frank-Raue K. Update multiple endocrine neoplasia type 2. Fam Cancer. 2010;9(3):449-57. doi:10.1007/s10689-010-9320-2 38. Scapineli JO, Ceolin L, Puñales MK, Dora JM, Maia AL. MEN 2A-related cutaneous lichen amyloidosis: report of three kindred and systematic literature review of clinical, biochemical and molecular characteristics. Fam Cancer. 2016;15(4):625-33. doi:10.1007/s10689-016-9892-6 39. Coyle D, Friedmacher F, Puri P. The association between Hirschsprung's disease and multiple endocrine neoplasia type 2a: a systematic review. Pediatr Surg Int. 2014;30(8):751-6. doi:10.1007/s00383-014-3538-2 40. Castinetti F, Waguespack SG, Machens A, Uchino S, Hasse-Lazar K, Sando G, et al. Natural history, treatment, and long-term follow up of patients with multiple endocrine neoplasia type 2B: an international, multicentre, retrospective study. Lancet Diabetes Endocrinol. 2019;7(3):213-20. doi:10.1016/S2213-8587(18)30336-X 41. Hadoux J, Pacini F, Tuttle RM, Schlumberger M. Management of advanced medullary thyroid cancer. Lancet Diabetes Endocrinol. 2016;4(1):64-71. doi:10.1016/S2213-8587(15)00337-X 42. Niederle MB, Scheuba C, Riss P, Selberherr A, Koperek O, Niederle B. Early Diagnosis of Medullary Thyroid Cancer: Are Calcitonin Stimulation Tests Still Indicated in the Era of Highly Sensitive Calcitonin Immunoassays? Thyroid. 2020;30(7):974-984. doi: 10.1089/thy.2019.0785. 43. Park H, Park J, Choi MS, Kim J, Kim H, Shin JH, et al. Preoperative Serum Calcitonin and Its Correlation with Extent of Lymph Node Metastasis in Medullary Thyroid Carcinoma. Cancers (Basel). 2020;12(10):2894. doi: 10.3390/cancers12102894. 44. Turkdogan S, Forest VI, Hier MP, Tamilia M, Florea A, Payne RJ. Carcinoembryonic antigen levels correlated with advanced disease in medullary thyroid cancer. J Otolaryngol Head Neck Surg. 2018;47(1):55. doi:10.1186/s40463-018-0303-x 45. Pacini F, Castagna MG, Cipri C, Schumberger M. Medullary thyroid carcinoma. Clin Oncol (R Coll Radiol). 2010;22(6):475-85. doi:10.1016/j.clon.2010.05.002 46. Machens A, Ukkat J, Hauptmann S, Dralle H. Abnormal carcinoembryonic antigen levels and medullary thyroid cancer progression: a multivariate analysis. Arch Surg. 2007;142(3):289-94. doi:10.1001/archsurg.142.3.289 47. Buzdugă CM, Costea CF, Cărăuleanu A, Lozneanu L, Turliuc MD, Cucu AI, et al. Protean cytological, histological and immunohistochemical appearances of medullary thyroid carcinoma: current updates. Rom J Morphol Embryol. 2019;60(2):369-81. 48. Klöppel G. Tumour biology and histopathology of neuroendocrine tumours. Best Pract Res Clin Endocrinol Metab. 2007;21(1):15-31. doi:10.1016/j.beem.2007.01.004 49. Agarwal S, Bychkov A, Jung CK. Emerging Biomarkers in thyroid practice and research. Cancers (Basel). 2021;14(1):204. doi:10.3390/cancers14010204 50. Tisell LE, Oden A, Muth A, Altiparmak G, Mõlne J, Ahlman H, et al. The Ki67 index a prognostic marker in medullary thyroid carcinoma. Br J Cancer. 2003;89(11):2093-7. doi:10.1038/sj.bjc.6601453 51. Mian C, Pennelli G, Barollo S, Altiparmak G, Mõlne J, Ahlman H, et al. Combined RET and Ki-67 assessment in sporadic medullary thyroid carcinoma: a useful tool for patient risk stratification. Eur J Endocrinol. 2011;164(6):971-6. doi:10.1530/EJE-11-0079 52. Xu B, Fuchs TL, Ahmadi S, Alghamdi M, Alzumaili B, Mohamed-Amine B, et al. International medullary thyroid carcinoma grading system: a validated grading system for medullary thyroid carcinoma. J Clin Oncol. 2022;40(1):96-104. doi:10.1200/JCO.21.01329 53. Takahashi M. Structure and expression of the ret transforming gene. IARC Sci Publ. 1988;(92):189-97. 54. Avantaggiato V, Dathan NA, Grieco M, Fabien N, Lazzaro D, Fusco A, et al. Developmental expression of the RET protooncogene. Cell Growth Differ. 1994;5(3):305-11. 55. Schuchardt A, D'Agati V, Larsson-Blomberg L, Costantini F, Pachnis V. Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret. Nature. 1994;367(6461):380-83. doi:10.1038/367380a0 56. Ikeda I, Ishizaka Y, Tahira T, Suzuki T, Onda M, Sugimura T, et al. Specific expression of the ret proto-oncogene in human neuroblastoma cell lines. Oncogene. 1990;5(9):1291-6. 57. Santoro M, Rosati R, Grieco M, Berlingieri MT, D'Amato GL, Franciscis V de, et al. The ret proto-oncogene is consistently expressed in human pheochromocytomas and thyroid medullary carcinomas. Oncogene. 1990;5(10):1595-8. 58. Takahashi M, Buma Y, Taniguchi M. Identification of the ret proto-oncogene products in neuroblastoma and leukemia cells. Oncogene. 1991;6(2):297-301. 59. Pasini B, Hofstra RM, Yin L, et al. The physical map of the human RET proto-oncogene. Oncogene. 1995;11(9):1737-1743. 60. 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. 1988;3(5):571-8. 61. Iwamoto T, Taniguchi M, Asai N, Ohkusu K, Nakashima I, Takahashi M. cDNA cloning of mouse ret proto-oncogene and its sequence similarity to the cadherin superfamily. Oncogene. 1993;8(4):1087-91. 62. Sugaya R, Ishimaru S, Hosoya T, Saigo K, Emori Y. A Drosophila homolog of human proto-oncogene ret transiently expressed in embryonic neuronal precursor cells including neuroblasts and CNS cells. Mech Dev. 1994;45(2):139-45. doi:10.1016/0925-4773(94)90027-2 63. Marcos-Gutiérrez CV, Wilson SW, Holder N, Pachnis V. The zebrafish homologue of the ret receptor and its pattern of expression during embryogenesis. Oncogene. 1997;14(8):879-89. doi:10.1038/sj.onc.1201048 64. Hahn M, Bishop J. Expression pattern of Drosophila ret suggests a common ancestral origin between the metamorphosis precursors in insect endoderm and the vertebrate enteric neurons. Proc Natl Acad Sci USA. 2001;98(3):1053-8. doi: 10.1073/ pnas.98.3.1053 65. Machens A, Lorenz K, Dralle H. Constitutive RET tyrosine kinase activation in hereditary medullary thyroid cancer: clinical opportunities. J Intern Med. 2009;266(1):114-25. doi:10.1111/j.1365-2796.2009.02113.x 66. Phay JE, Shah MH. Targeting RET receptor tyrosine kinase activation in cancer. Clin Cancer Res. 2010;16(24):5936-41. doi:10.1158/1078-0432.CCR-09-0786 67. Anders J, Kjar S, Ibáñez CF. Molecular modeling of the extracellular domain of the RET receptor tyrosine kinase reveals multiple cadherin-like domains and a calcium-binding site. J Biol Chem. 2001;276(38):35808-17. doi:10.1074/jbc.M104968200 68. Mahato AK, Sidorova YA. RET receptor tyrosine kinase: role in neurodegeneration, obesity, and cancer. Int J Mol Sci. 2020;21(19):7108. doi:10.3390/ijms21197108 69. Ibáñez CF. Structure and physiology of the RET receptor tyrosine kinase. Cold Spring Harb Perspect Biol. 2013;5(2):a009134. doi:10.1101/cshperspect.a009134 70. Takahashi M, Asai N, Iwashita T, Isomura T, Miyazaki K, Matsuyama M. Characterization of the ret proto-oncogene products expressed in mouse L cells. Oncogene. 1993;8(11):2925-9. 71. Rochette L, Zeller M, Cottin Y, Vergely C. Insights into mechanisms of GDF15 and receptor gfral: therapeutic targets. Trends Endocrinol Metab. 2020;31(12):939-51. doi:10.1016/j.tem.2020.10.004 72. Tahira T, Ishizaka Y, Itoh F, Sugimura T, Nagao M. Characterization of ret proto-oncogene mRNAs encoding two isoforms of the protein product in a human neuroblastoma cell line. Oncogene. 1990;5(1):97-102. 73. Myers SM, Eng C, Ponder BA, Mulligan LM. Characterization of RET proto-oncogene 3' splicing variants and polyadenylation sites: a novel C-terminus for RET. Oncogene. 1995;11(10):2039-45. 74. Carter MT, Yome JL, Marcil MN, Martin CA, Vanhorne JB, Mulligan LM. Conservation of RET proto-oncogene splicing variants and implications for RET isoform function. Cytogenet Cell Genet. 2001;95(3-4):169-176. doi:10.1159/000059341 75. Pachnis V, Mankoo B, Costantini F. Expression of the c-ret proto-oncogene during mouse embryogenesis. Development. 1993;119(4):1005-17. doi:10.1242/dev.119.4.1005 76. Tsuzuki T, Takahashi M, Asai N, Iwashita T, Matsuyama M, Asai J. Spatial and temporal expression of the ret proto-oncogene product in embryonic, infant and adult rat tissues. Oncogene. 1995;10(1):191-8. 77. Trupp M, Belluardo N, Funakoshi H, Ibáñez CF. Complementary and overlapping expression of glial cell line-derived neurotrophic factor (GDNF), c-ret proto-oncogene, and GDNF receptor-alpha indicates multiple mechanisms of trophic actions in the adult rat CNS. J Neurosci. 1997;17(10):3554-67. doi:10.1523/JNEUROSCI.17-10-03554.1997 78. Bennett DL, Michael GJ, Ramachandran N, Munson JB, Averill S, Yan Q, et al. A distinct subgroup of small DRG cells express GDNF receptor components and GDNF is protective for these neurons after nerve injury. J Neurosci. 1998;18(8):3059-72. doi:10.1523/JNEUROSCI.18-08-03059.1998 79. Ichihara M, Murakumo Y, Takahashi M. RET and neuroendocrine tumors. Cancer Lett. 2004;204(2):197-211. doi:10.1016/S0304-3835(03)00456-7 80. Schuchardt A, D'Agati V, Pachnis V, Costantini F. Renal agenesis and hypodysplasia in ret-k- mutant mice result from defects in ureteric bud development. Development. 1996;122(6):1919-29. doi:10.1242/dev.122.6.1919 81. Chi X, Michos O, Shakya R, Riccio P, Enomoto H, Licht JD, et al. Ret-dependent cell rearrangements in the wolffian duct epithelium initiate ureteric bud morphogenesis. Dev Cell. 2009;17(2):199-209. doi:10.1016/j.devcel.2009.07.013 82. Davis TK, Hoshi M, Jain S. To bud or not to bud: the RET perspective in CAKUT. Pediatr Nephrol. 2014;29(4):597-608. doi:10.1007/s00467-013-2606-5 83. Meng X, Lindahl M, Hyvönen ME, Parvinen M, Rooij MD de, Hess MW, et al. Regulation of cell fate decision of undifferentiated spermatogonia by GDNF. Science. 2000;287(5457):1489-93. doi:10.1126/science.287.5457.1489 84. Naughton CK, Jain S, Strickland AM, Gupta A, Milbrandt J. Glial cell-line derived neurotrophic factor-mediated RET signaling regulates spermatogonial stem cell fate. Biol Reprod. 2006;74(2):314-21. doi:10.1095/biolreprod.105.047365 85. Jijiwa M, Kawai K, Fukihara J, Nakamura A, Hasegawa M, Suzuki C, et al. GDNF-mediated signaling via RET tyrosine 1062 is essential for maintenance of spermatogonial stem cells. Genes Cells. 2008;13(4):365-74. doi:10.1111/j.1365-2443.2008.01171. 86. Airaksinen MS, Saarma M. The GDNF family: signalling, biological functions and therapeutic value. Nat Rev Neurosci. 2002;3(5):383-94. doi:10.1038/nrn812 87. Accardo G, Conzo G, Esposito D, Gambardella C, Mazzella M, Castaldo F, et al. Genetics of medullary thyroid cancer: an overview. Int J Surg. 2017;41:(Suppl 1):S2-S6. doi:10.1016/j.ijsu.2017.02.064 88. Mulligan LM, Kwok JB, Healey CS, Elsdon MJ, Eng C, Gardner E, et al. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature. 1993;363(6428):458-60. doi:10.1038/363458a0 89. Donis-Keller H, Dou S, Chi D, Carlson KM, Toshima K, Lairmore, TC, et al. Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet. 1993;2(7):851-6. doi:10.1093/hmg/2.7.851 90. Li SY, Ding YQ, Si YL, Ye MJ, Xu CM, Qi XP. 5P Strategies for Management of Multiple Endocrine Neoplasia Type 2: A Paradigm of Precision Medicine. Front Endocrinol (Lausanne). 2020;11:543246. doi:10.3389/fendo.2020.543246 91. Raue F, Frank-Raue K. Genotype-phenotype correlation in multiple endocrine neoplasia type 2. Clinics (Sao Paulo). 2012;67(Suppl 1):69-75. doi: 10.6061 clinics/2012(sup01)13 92. Asai N, Iwashita T, Matsuyama M, Takahashi M. Mechanism of activation of the ret proto-oncogene by multiple endocrine neoplasia 2A mutations. Mol Cell Biol. 1995;15(3):1613-9. doi:10.1128/MCB.15.3.1613 93. Santoro M, Carlomagno F, Romano A, Bottaro DP, Dathan NA, Grieco M, et al. Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science. 1995;267(5196):381-3. doi:10.1126/science.7824936 94. Rothberg AE, Raymond VM, Gruber SB, Sisson J. Familial medullary thyroid carcinoma associated with cutaneous lichen amyloidosis. Thyroid. 2009;19(6):651-5. doi:10.1089/thy.2009.0021 95. Qi XP, Peng JZ, Yang XW, Cao Z-L, Yu X-H, Fang X-D, et al. The RET C611Y mutation causes MEN 2A and associated cutaneous. Endocr Connect. 2018;7(9):998-1005. doi:10.1530/EC-18-0220 96. Frank-Raue K, Rybicki LA, Erlic Z, Schweizer H, Winter A, Milos I, et al. Risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germline RET mutations located in exon 10. Hum Mutat. 2011;32(1):51-8. doi:10.0002/ humu.21385 97. Raue F, Frank-Raue K. Genotype-phenotype relationship in multiple endocrine neoplasia type 2. Implications for clinical management. Hormones (Athens). 2009;8(1):23-8. doi:10.14310/horm.2002.1218 98. Carlson KM, Dou S, Chi D, Scavarda N, Toshima K, Jackson CE, et al. Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B. Proc Natl Acad Sci USA. 1994;91(4):1579-83. doi:10.1073/pnas.91.4.1579 99. Smith DP, Houghton C, Ponder BA. Germline mutation of RET codon 883 in two cases of de novo MEN 2B. Oncogene. 1997;15(10):1213-17. doi:10.1038/sj.onc.1201481 100. Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF, 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(19):1575-9. doi:10.1001/jama.1996.03540190047028 101. Gimm O, Marsh DJ, Andrew SD, Frilling A, Dahia PL, Mulligan LM, et al. Germline dinucleotide mutation in codon 883 of the RET proto-oncogene in multiple endocrine neoplasia type 2B without codon 918 mutation. J Clin Endocrinol Metab. 1997;82(11):3902-4. doi:10.1210/jcem.82.11.4508 102. Mathiesen JS, Habra MA, Bassett JHD, Choudhury M, Balasubramanian SP, Howlett TA, et al. Risk profile of the RET A883F germline mutation: an international collaborative study. J Clin Endocrinol Metab. 2017;102(6):2069-74. doi:10.1210/jc.2016-3640 103. Songyang Z, Carraway KL 3rd, Eck MJ, Harrison SC, Feldman RA, Mohammadi M, et al. Catalytic specificity of protein-tyrosine kinases is critical for selective signalling. Nature. 1995;373(6514):536-9. doi:10.1038/373536a0 104. Gujral TS, Singh VK, Jia Z, Mulligan LM. Molecular mechanisms of RET receptor-mediated oncogenesis in multiple endocrine neoplasia 2B. Cancer Res. 2006;66(22):10741-9. doi:10.1158/0008-5472.CAN-06-3329 105. Knowles PP, Murray-Rust J, Kjaer S, Scott RP, Hanrahan S, Santoro M, et al. Structure and chemical inhibition of the RET tyrosine kinase domain. J Biol Chem. 2006;281(44):33577-87. doi: 10.1074/jbc. M605604200 106. Cranston AN, Carniti C, Oakhill K, Radzio-Andzelm E, Stone EA, McCallionet AS, al. RET is constitutively activated by novel tandem mutations that alter the active site resulting in multiple endocrine neoplasia type 2B. Cancer Res. 2006;66(20):10179-87. doi:10.1158/0008-5472.CAN-06-0884 107. Miyauchi A, Futami H, Hai N, Radzio-Andzelm E, Stone EA, McCallion AS, et al. Two germline missense mutations at codons 804 and 806 of the RET proto-oncogene in the same allele in a patient with multiple endocrine neoplasia type 2B without codon 918 mutation. Jpn J Cancer Res. 1999;90(1):1-5. doi:10.1111/j.1349-7006.1999.tb00658.x 108. Iwashita T, Murakami H, Kurokawa K, Kawai K, Miyauchi A, Futami H, et al. A two-hit model for development of multiple endocrine neoplasia type 2B by RET mutations. Biochem Biophys Res Commun. 2000;268(3):804-08. doi:10.1006/ bbrc.2000.2227 109. Kameyama K, Okinaga H, Takami H. RET oncogene mutations in 75 cases of familial medullary thyroid carcinoma in Japan. Biomed Pharmacother. 2004;58(6-7):345-7. doi:10.1016/j.biopha.2004.05.001 110. Nakao KT, Usui T, Ikeda M, Mori Y, Yamamoto T, Kawashima S-T, et al. Novel tandem germline RET proto-oncogene mutations in a patient with multiple endocrine neoplasia type 2B: report of a case and a literature review of tandem RET mutations with in silico analysis. Head Neck. 2013;35(12):E363-8. doi:10.1002/hed.23241 111. Mathew A, Latteyer S, Frank-Raue K, Moeller LC, Zwanziger D, Mengel M, et al. A Novel double RET E768D/L790F mutation associated with a MEN2B-Like phenotype. Thyroid. 2021;31(2):327-9. doi:10.1089/thy.2019.0472 112. Eng C, Mulligan LM, Healey CS, Houghton C, Frilling A, Raue F, et al. Heterogeneous mutation of the RET proto-oncogene in subpopulations of medullary thyroid carcinoma. Cancer Res. 1996;56(9):2167-70. 113. Eng C, Mulligan LM, Smith DP, Healey CS, Frilling A, Raue F, et al. Mutation of the RET protooncogene in sporadic medullary thyroid carcinoma. Genes Chromosomes Cancer. 1995;12(3):209-12. doi:10.1002/gcc.2870120308 114. Marsh DJ, Learoyd DL, Andrew SD, Krishnan L, Pojer R, Richardson AL, et al. Somatic mutations in the RET proto-oncogene in sporadic medullary thyroid carcinoma. Clin Endocrinol (Oxf). 1996;44(3):249-57. doi:10.1046/j.1365-2265.1996.681503.x 115. 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. doi:10.1210/jcem.81.4.8636377 116. Dvorakova S, Vaclavikova E, Sykorova V, Vcelak J, Novak Z, Duskova J, et al. Somatic mutations in the RET proto-oncogene in sporadic medullary thyroid carcinomas. Mol Cell Endocrinol. 2008;284(1-2):21-7. doi:10.1016/j.mce.2007.12.016 117. 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):682-7. doi:10.1210/jc.2007-1714 118. Moura MM, Cavaco BM, Pinto AE, Domingues R, Santos JR, Cid MO, et al. Correlation of RET somatic mutations with clinicopathological features in sporadic medullary thyroid carcinomas. Br J Cancer. 2009;100(11):1777-83. doi:10.1038/sj.bjc.6605056 119. Romei C, Ciampi R, Casella F, Tacito A, Torregrossa L, Ugolini C, et al. RET mutation heterogeneity in primary advanced medullary thyroid cancers and their metastases. Oncotarget. 2018;9(11):9875-84. doi:10.18632/oncotarget.23986 120. Mulligan LM, Marsh DJ, Robinson BG, Schuffenecker I, Zedenius J, Lips CJM, et al. Genotype-phenotype correlation in multiple endocrine neoplasia type 2: report of the International RET Mutation Consortium. J Intern Med. 1995;238(4):343-6. doi:10.1111/j.1365-2796.1995.tb01208.x 121. Machens A, Gimm O, Hinze R, Höppner W, Boehm BO, Dralle H. Genotype-phenotype correlations in hereditary medullary thyroid carcinoma: oncological features and biochemical properties. J Clin Endocrinol Metab. 2001;86(3):1104-9. doi:10.1210/jcem.86.3.7290 122. Yip L, Cote GJ, Shapiro SE, Ayers GD, Herzog CE, Sellin RV, et al. Multiple endocrine neoplasia type 2: evaluation of the genotype-phenotype relationship. Arch Surg. 2003;138(4):409-16. doi:10.1001/archsurg.138.4.409 123. Milos IN, Frank-Raue K, Wohllk N, Maia AL, Pusiol E, Patocs A, et al. Age-related neoplastic risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germ line RET Cys634Trp (TGC>TGG) mutation. Endocr Relat Cancer. 2008;15(4):1035-41. doi:10.1677/ERC-08-0105 124. Schuffenecker I, Virally-Monod M, Brohet R, Goldgar D, Conte-Devolx B, Leclerc L, et al. Risk and penetrance of primary hyperparathyroidism in multiple endocrine neoplasia type 2A families with mutations at codon 634 of the RET proto-oncogene. J Clin Endocrinol Metab. 1998;83(2):487-91. doi:10.1210/jcem.83.2.4529 125. Puñales MK, Graf H, Gross JL, Maia AL. RET codon 634 mutations in multiple endocrine neoplasia type 2: variable clinical features and clinical outcome. J Clin Endocrinol Metab. 2003;88(6):2644-9. doi:10.1210/jc.2002-021422 126. Jasim S, Ying AK, Waguespack SG, Rich TA, Grubbs EG, Jimenez C, et al. Multiple endocrine neoplasia type 2B with a RET proto-oncogene A883F mutation displays a more indolent form of medullary thyroid carcinoma compared with a RET M918T mutation. Thyroid. 2011;21(2):189-92. doi:10.1089/thy.2010.0328 127. Schilling T, Bürck J, Sinn HP, Clemens A. Prognostic value of codon 918 (ATG-->ACG) RET proto-oncogene mutations in sporadic medullary thyroid carcinoma. Int J Cancer. 2001;95(1):62-6. doi:10.1002/1097-0215(20010120)95:1<62::aid-ijc1011>3.0.co;2-1 128. Romei C, Ugolini C, Cosci B, Torregrossa L, Vivaldi A, Ciampi R, et al. Low prevalence of the somatic M918T RET mutation in micro-medullary thyroid cancer. Thyroid. 2012;22(5):476-81. doi:10.1089/thy.2011.0358 129. Raue F, Frank-Raue K. Update on multiple endocrine neoplasia type 2: focus on medullary thyroid carcinoma. J Endocr Soc. 2018;2(8):933-43.doi:10.1210/js.2018-00178 130. Lombardo F, Baudin E, Chiefari E, Arturi F, Bardet S, Caillou B, et al. Familial medullary thyroid carcinoma: clinical variability and low aggressiveness associated with RET mutation at codon 804. J Clin Endocrinol Metab. 2002;87(4):1674-80. doi:10.1210/jcem.87.4.8403 131. Lindskog S, Nilsson O, Jansson S, Illerskog A-C, Ysander L, Ahlman H, et al. Phenotypic expression of a family with multiple endocrine neoplasia type 2A due to a RET mutation at codon 618. Br J Surg. 2004;91(6):713-8. doi:10.1002/bjs.4457 132. Signorini PS, França MI, Camacho CP, Lindsey SC, Valente FOF, Kasamatsu TS, et al. A ten-year clinical update of a large RET p.Gly533Cys kindred with medullary thyroid carcinoma emphasizes the need for an individualized assessment of affected relatives. Clin Endocrinol (Oxf). 2014;80(2):235-45. doi:10.1111/cen.12264 133. Long KL, Etzel C, Rich T, et al. All in the family? Analyzing the impact of family history in addition to genotype on medullary thyroid carcinoma aggressiveness in MEN2A patients. Fam Cancer. 2017;16(2):283-9. doi:10.1007/s10689-016-9948-7 134. Machens A, Lorenz K, Weber F, Dralle H. Genotype-specific progression of hereditary medullary thyroid cancer. Hum Mutat. 2018;39(6):860-9. doi:10.1002/humu.23430 135. Mathiesen JS, Nielsen SG, Rasmussen ÅK, Kiss K, Wadt K, Hermann AP, et al. Variability in medullary thyroid carcinoma in ret l790f carriers: a case comparison study of index patients. Front Endocrinol. 2020;11(251):1-7. doi:10.3389/fendo.2020.00251 136. Colombo C, Minna E, Rizzetti MG, et al. The modifier role of RET-G691S polymorphism in hereditary medullary thyroid carcinoma: functional characterization and expression/penetrance studies. Orphanet J Rare Dis. 2015;10:25. doi:10.1186/s13023-015-0231-z 137. Cebrian A, Lesueur F, Martin S, et al. Polymorphisms in the initiators of RET (rearranged during transfection) signaling pathway and susceptibility to sporadic medullary thyroid carcinoma. J Clin Endocrinol Metab. 2005;90(11):6268-6274. doi:10.1210/jc.2004-2449 138. Robledo M, Gil L, Pollán M, et al. Polymorphisms G691S/S904S of RET as genetic modifiers of MEN 2A. Cancer Res. 2003;63(8):1814-1817. 139. Elisei R, Cosci B, Romei C, et al. RET exon 11 (G691S) polymorphism is significantly more frequent in sporadic medullary thyroid carcinoma than in the general population. J Clin Endocrinol Metab. 2004;89(7):3579-3584. doi:10.1210/jc.2003-031898 140. Lebeault M, Pinson S, Guillaud-Bataille M, et al. Nationwide French Study of RET Variants Detected from 2003 to 2013 Suggests a Possible Influence of Polymorphisms as Modifiers. Thyroid. 2017;27(12):1511-1522. doi:10.1089/thy.2016.0399 141. Magalhães PK, de Castro M, Elias LL, Soares EG, Maciel LM. Polymorphisms in the RET proto-oncogene and the phenotypic presentation of familial medullary thyroid carcinoma. Thyroid. 2004;14(10):848-852. doi:10.1089/thy.2004.14.848 142. Wiench M, Wygoda Z, Gubala E, et al. Estimation of risk of inherited medullary thyroid carcinoma in apparent sporadic patients. J Clin Oncol. 2001;19(5):1374-1380. doi:10.1200/JCO.2001.19.5.1374 143. Sromek M, Czetwertyńska M, Skasko E, Zielińska J, Czapczak D, Steffen J. The frequency of selected polymorphic variants of the RET gene in patients with medullary thyroid carcinoma and in the general population of central. Poland. Endocr Pathol. 2010;21(3):178-185. doi:10.1007/s12022-010-9125-8 144. Siqueira DR, Romitti M, da Rocha AP, et al. The RET polymorphic allele S836S is associated with early metastatic disease in patients with hereditary or sporadic medullary thyroid carcinoma. Endocr Relat Cancer. 2010;17(4):953-963. doi:10.1677/ERC-09-0312 145. Ceolin L, Siqueira DR, Ferreira CV, et al. Additive effect of RET polymorphisms on sporadic medullary thyroid carcinoma susceptibility and tumor aggressiveness. Eur J Endocrinol. 2012;166(5):847-854. doi:10.1530/EJE-11-1060 146. Machens A, Frank-Raue K, Lorenz K, Rondot S, Raue F, Dralle H. Clinical relevance of RET variants G691S, L769L, S836S and S904S to sporadic medullary thyroid cancer. Clin Endocrinol (Oxf). 2012;76(5):691-697. doi:10.1111/j.1365-2265.2011.04293.x 147. Zhang Y, Wang S, Chen X, Huang S, Li J. Quantitative assessment of the association between L769L and S836S polymorphisms at RET gene and medullary thyroid carcinoma risk. Tumour Biol. 2014;35(7):6641-6647. doi:10.1007/s13277-014-1878-0 148. Skalniak A, Trofimiuk-Müldner M, Przybylik-Mazurek E, Hubalewska-Dydejczyk A. Modifier Role of Common RET Variants in Sporadic Medullary Thyroid Carcinoma. Int J Mol Sci. 2021 Oct 30;22(21):11794. doi: 10.3390/ijms222111794. 149. Berard I, Kraimps JL, Savagner F, et al. Germline-sequence variants S836S and L769L in the RE arranged during Transfection (RET) proto-oncogene are not associated with predisposition to sporadic medullary carcinoma in the French population. Clin Genet. 2004;65(2):150-152. doi:10.1111/j.0009-9163.2004.00172.x 150. Baumgartner-Parzer SM, Lang R, Wagner L, et al. Polymorphisms in exon 13 and intron 14 of the RET protooncogene: genetic modifiers of medullary thyroid carcinoma?. J Clin Endocrinol Metab. 2005;90(11):6232-6236. doi:10.1210/jc.2005-1278 151. Wohllk, N; Soto, E; Bravo, M; Becker, P. G691S, L769L and S836S ret proto-oncogene polymorphisms are not associated with higher risk to sporadic medullary thyroid carcinoma in Chilean patients. Rev. Méd. Chile. 2005;133(4):397-402. http://dx.doi.org/10.4067/S0034-98872005000400001. 152. Weinhaeusel A, Scheuba C, Lauss M, et al. The influence of gender, age, and RET polymorphisms on C-cell hyperplasia and medullary thyroid carcinoma. Thyroid. 2008;18(12):1269-1276. doi:10.1089/thy.2008.0139 153. Sharma BP, Saranath D. RET gene mutations and polymorphisms in medullary thyroid carcinomas in Indian patients. J Biosci. 2011;36(4):603-611. doi:10.1007/s12038-011-9095-0 154. Lantieri F, Caroli F, Ceccherini I, Griseri P. The involvement of the RET variant G691S in medullary thyroid carcinoma enlightened by a meta-analysis study. Int J Cancer. 2013;132(12):2808-2819. doi:10.1002/ijc.27967 155. Rocha, AP; Magalhães, PK; Maia, AL; Maciel, LM. Genetic polymorphisms: implications in the pathogenesis of medullary thyroid carcinoma. Arq. Bras. Endocrinol. Metab. 2007; 51(5):723-730. https://doi.org/10.1590/S0004-27302007000500009 156. Ceolin, L.; Siqueira, D.R.; Romitti, M.; Ferreira, C.V.; Maia, A.L. Molecular Basis of Medullary Thyroid Carcinoma: The Role of RET Polymorphisms. Int. J. Mol. Sci. 2012;13(1):221-239. https://doi.org/10.3390/ijms13010221 157. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-24. doi: 10.1038/gim.2015.30. 158. Brierley J, Gospodarowicz M, Wittekind C, editors. TNM classification of malignant tumours. Chichester: Wiley; 2017. 159. Amodru V, Taieb D, Guerin C, Romanet P, Paladino N, Brue T, et al. MEN2-related pheochromocytoma: current state of knowledge, specific characteristics in MEN2B, and perspectives. Endocrine. 2020;69(3):496-503. doi: 10.1007/s12020-020-02332-2. 160. Inabnet WB, Caragliano P, Pertsemlidis D. Pheochromocytoma: inherited associations, bilaterality, and cortex preservation. Surgery. 2000;128(6):1007-1012. doi: 10.1067/msy.2000.110846. 161. Rodriguez JM, Balsalobre M, Ponce JL, Ríos A, Torregrosa NM, Tebar J, et al. Pheochromocytoma in MEN 2A syndrome. Study of 54 patients. World J Surg. 2008;32(11):2520-6. doi: 10.1007/s00268-008-9734-2. 162. Frank-Raue K, Rybicki LA, Erlic Z, Schweizer H, Winter A, Milos I, et al. International RET Exon 10 Consortium. Risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germline RET mutations located in exon 10. Hum Mutat. 2011;32(1):51-8. doi: 10.1002/humu.21385. PMID: 20979234. 163. Imai T, Uchino S, Okamoto T, Suzuki S, Kosugi S, Kikumori T, et al. MEN Consortium of Japan. High penetrance of pheochromocytoma in multiple endocrine neoplasia 2 caused by germ line RET codon 634 mutation in Japanese patients. Eur J Endocrinol. 2013;168(5):683-7. doi: 10.1530/EJE-12-1106. 164. Ruiz-Ferrer M, Fernández RM, Antiñolo G, López-Alonso M, Eng C, Borrego S. A complex additive model of inheritance for Hirschsprung disease is supported by both RET mutations and predisposing RET haplotypes. Genet Med. 2006;8(11):704-10. doi: 10.1097/01.gim.0000245632.06064.f1. 165. Frank-Raue K, Döhring J, Scheumann G, Rondot S, Lorenz A, Schulze E, et al. New mutations in the RET protooncogene-L881V - associated with medullary thyroid carcinoma and -R770Q - in a patient with mixed medullar/follicular thyroid tumour. Exp Clin Endocrinol Diabetes. 2010;118(8):550-3. doi: 10.1055/s-0029-1241851. 166. Brandão LG, Cavalheiro BG, Junqueira CR. Prognostic influence of clinical and pathological factors in medullary thyroid carcinoma: a study of 53 cases. Clinics (Sao Paulo). 2009;64(9):849-56. doi: 10.1590/S1807-59322009000900005. 167. Martins-Costa MC, Lindsey SC, Cunha LL, Carreiro-Filho FP, Cortez AP, Holanda ME, et al. A pioneering RET genetic screening study in the State of Ceará, Brazil, evaluating patients with medullary thyroid cancer and at-risk relatives: experience with 247 individuals. Arch Endocrinol Metab. 2018;62(6):623-635. doi: 10.20945/2359-3997000000088. 168. Raue F. German medullary thyroid carcinoma/multiple endocrine neoplasia registry. Langenbecks Arch Surg. 1998;383(5):334-336. doi: 10.1007/s004230050143. 169. Correia-Deur JE, Toledo RA, Imazawa AT, Lourenço DM Jr, Ezabella MC, Tavares MR, Toledo SP. Sporadic medullary thyroid carcinoma: clinical data from a university hospital. Clinics (Sao Paulo). 2009;64(5):379-86. doi: 10.1590/s1807-59322009000500002. 170. Cavalheiro BG, Matos LL, Leite AK, Kulcsar MA, Cernea CR, Brandão LG. Surgical treatment for thyroid carcinoma: retrospective study with 811 patients in a Brazilian tertiary hospital. Arch Endocrinol Metab. 2016;60(5):472-478. doi: 10.1590/2359-3997000000209. 171. Brandwein-Gensler M, Urken M, Wang B. Collision tumor of the thyroid: a case report of metastatic liposarcoma plus papillary thyroid carcinoma. Head Neck. 2004;26(7):637-41. doi: 10.1002/hed.20024. 172. Rossi S, Fugazzola L, De Pasquale L, Braidotti P, Cirello V, Beck-Peccoz P, et al. Medullary and papillary carcinoma of the thyroid gland occurring as a collision tumour: report of three cases with molecular analysis and review of the literature. Endocr Relat Cancer. 2005;12(2):281-9. doi: 10.1677/erc.1.00901. 173. Dikbas O, Duman AA, Guvendi GF. Medullary Thyroid Carcinoma and Papillary Thyroid Carcinoma in the Same Patient as a Collision Tumour. Case Rep Endocrinol. 2019;2019:4038628. doi: 10.1155/2019/4038628. 174. Thomas A, Mittal N, Rane SU, Bal M, Patil A, Ankathi SK, Vaish R. Papillary and Medullary Thyroid Carcinomas Presenting as Collision Tumors: A Case Series of 21 Cases at a Tertiary Care Cancer Center. Head Neck Pathol. 2021;15(4):1137-1146. doi: 10.1007/s12105-021-01323-7. 175. Mousa U, Gursoy A, Ozdemir H, Moray G. Medullary thyroid carcinoma in a patient with Hashimoto's thyroiditis diagnosed by calcitonin washout from a thyroid nodule. Diagn Cytopathol. 2013;41(7):644-6. doi: 10.1002/dc.21850. 176. Zayed AA, Ali MK, Jaber OI, Suleiman MJ, Ashhab AA, Al Shweiat WM, et al. Is Hashimoto's thyroiditis a risk factor for medullary thyroid carcinoma? Our experience and a literature review. Endocrine. 2015;48(2):629-36. doi: 10.1007/s12020-014-0363-2. 177. Dasgupta S, Chakrabarti S, Mandal PK, Das S. Hashimoto's Thyroiditis and Medullary Carcinoma of Thyroid. JNMA J Nepal Med Assoc. 2014;52(194):831-3. 178. Malpani S, Tandon A, Panwar H, Khurana U, Kapoor N, Behera G, Gupta V. Medullary thyroid carcinoma co-existent with Hashimoto's thyroiditis diagnosed by a comprehensive cytological approach. Diagn Cytopathol. 2020;48(4):386-389. doi: 10.1002/dc.24373. 179. Maciel RMB, Maia AL. Global endocrinology: Geographical variation in the profile of RET variants in patients with medullary thyroid cancer: a comprehensive review. Eur J Endocrinol. 2021;186(1):R15-R30. doi: 10.1530/EJE-21-0753. 180. Maciel RMB, Camacho CP, Assumpção LVM, Bufalo NE, Carvalho AL, Carvalho GA, et al. Genotype and phenotype landscape of MEN2 in 554 medullary thyroid cancer patients: the BrasMEN study. Endocr Connect. 2019;8(3):289-298. doi: 10.1530/EC-18-0506. 181. Siqueira DR, Ceolin L, Ferreira CV, Romitti M, Maia SC, Maciel LM, et al. Role of RET genetic variants in MEN2-associated pheochromocytoma. Eur J Endocrinol. 2014;170(6):821-8. doi: 10.1530/EJE-14-0084. 182. Costa P, Domingues R, Sobrinho LG, Bugalho MJ. RET polymorphisms and sporadic medullary thyroid carcinoma in a Portuguese population. Endocrine. 2005;27(3):239-43. doi: 10.1385/ENDO:27:3:239. 183. Hatanaka R. Rastreamento de variantes de significado desconhecido (VUS) no gene RET em indivíduos-controle e em pacientes com carcinoma medular de tireoide. [dissertação]. São Paulo: Faculdade de Medicina, Universidade de São Paulo, 2015. 184. Ministério da Saúde. Portaria nº 874 de 16 de maio de 2013. Institui a política nacional para a prevenção e controle do câncer na Rede de Atenção à Saúde das Pessoas com Doenças Crônicas no âmbito do Sistema Único de Saúde (SUS). Brasil: 2013. 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dc.title.pt_BR.fl_str_mv Caracterização clínica e molecular de pacientes com carcinoma medular de tireoide do estado da Bahia
dc.title.alternative.pt_BR.fl_str_mv Clinical and molecular characterization of patients with medullary carcinoma of the thyroid in the state of Bahia
title Caracterização clínica e molecular de pacientes com carcinoma medular de tireoide do estado da Bahia
spellingShingle Caracterização clínica e molecular de pacientes com carcinoma medular de tireoide do estado da Bahia
Matta, Rafael Reis Campos da
CNPQ::CIENCIAS BIOLOGICAS::GENETICA::GENETICA HUMANA E MEDICA
Carcinoma medular
Mutação
Polimorfismo de nucleotídeo único
Tireoidectomia
Medullary carcinoma
Mutation
Single-nucleotide polymorphism
Thyroidectomy
title_short Caracterização clínica e molecular de pacientes com carcinoma medular de tireoide do estado da Bahia
title_full Caracterização clínica e molecular de pacientes com carcinoma medular de tireoide do estado da Bahia
title_fullStr Caracterização clínica e molecular de pacientes com carcinoma medular de tireoide do estado da Bahia
title_full_unstemmed Caracterização clínica e molecular de pacientes com carcinoma medular de tireoide do estado da Bahia
title_sort Caracterização clínica e molecular de pacientes com carcinoma medular de tireoide do estado da Bahia
author Matta, Rafael Reis Campos da
author_facet Matta, Rafael Reis Campos da
author_role author
dc.contributor.advisor1.fl_str_mv Ramos, Helton Estrela
dc.contributor.advisor1ID.fl_str_mv https://orcid.org/0000-0002-2900-2099
dc.contributor.advisor1Lattes.fl_str_mv http://lattes.cnpq.br/5624505454133902
dc.contributor.advisor-co1.fl_str_mv Cerqueira, Taíse Lima de Oliveira
dc.contributor.advisor-co1Lattes.fl_str_mv http://lattes.cnpq.br/0365632293236220
dc.contributor.referee1.fl_str_mv Ramos, Helton Estrela
dc.contributor.referee1ID.fl_str_mv https://orcid.org/0000-0002-2900-2099
dc.contributor.referee1Lattes.fl_str_mv http://lattes.cnpq.br/5624505454133902
dc.contributor.referee2.fl_str_mv Carvalho, Acacia Fernandes Lacerda de
dc.contributor.referee2ID.fl_str_mv https://orcid.org/0000-0003-3639-338X
dc.contributor.referee2Lattes.fl_str_mv http://lattes.cnpq.br/8227096712575197
dc.contributor.referee3.fl_str_mv Camacho, Cléber Pinto
dc.contributor.referee3ID.fl_str_mv https://orcid.org/0000-0002-8653-0031
dc.contributor.referee3Lattes.fl_str_mv http://lattes.cnpq.br/1832800364435894
dc.contributor.authorLattes.fl_str_mv http://lattes.cnpq.br/1369558540098706
dc.contributor.author.fl_str_mv Matta, Rafael Reis Campos da
contributor_str_mv Ramos, Helton Estrela
Cerqueira, Taíse Lima de Oliveira
Ramos, Helton Estrela
Carvalho, Acacia Fernandes Lacerda de
Camacho, Cléber Pinto
dc.subject.cnpq.fl_str_mv CNPQ::CIENCIAS BIOLOGICAS::GENETICA::GENETICA HUMANA E MEDICA
topic CNPQ::CIENCIAS BIOLOGICAS::GENETICA::GENETICA HUMANA E MEDICA
Carcinoma medular
Mutação
Polimorfismo de nucleotídeo único
Tireoidectomia
Medullary carcinoma
Mutation
Single-nucleotide polymorphism
Thyroidectomy
dc.subject.por.fl_str_mv Carcinoma medular
Mutação
Polimorfismo de nucleotídeo único
Tireoidectomia
dc.subject.other.pt_BR.fl_str_mv Medullary carcinoma
Mutation
Single-nucleotide polymorphism
Thyroidectomy
description Introdução: O carcinoma medular de tireoide é um câncer raro que tem origem nas células C e pode se apresentar na forma esporádica (75%) ou hereditária (25%), como componente das síndromes de neoplasia endócrina múltipla tipo 2. Tanto a doença esporádica quanto a doença hereditária têm como principal causa as mutações no proto-oncogene RET. Sua incidência e suas bases moleculares ainda são desconhecidas e pouco investigadas, sobretudo em estados do Nordeste do país. Na Bahia, ainda não há registro de estudos que tenham investigado o comportamento e as características dessa doença na região. Objetivo: Caracterizar clínica e molecularmente pacientes com carcinoma medular de tireoide no estado da Bahia. Metodologia: Estudo transversal e descritivo que envolveu pacientes com diagnóstico histopatológico da doença, encaminhados para realização do teste molecular, no período de 2020 a 2022. Os dados clínicos-patológicos foram coletados a partir dos laudos anatomopatológicos e imuno-histoquímicos dos pacientes. O DNA genômico foi extraído a partir do sangue periférico. Os éxons 10, 11, 13, 14 e 15 do RET foram amplificados por reação em cadeia da polimerase e, posteriormente, sequenciados pelo método de Sanger. Resultados: Incluíram-se 29 pacientes no estudo (82,8% do sexo feminino). A idade média do diagnóstico foi de 46,5 ± 13,1 anos e o tamanho médio do tumor de 2,1 ± 1,4 cm. Invasão capsular, invasão extratireoidiana e invasão angiolinfática ocorreram em 13,8%, 3,4% e 6,9% dos casos, respectivamente. De acordo com a classificação TNM, 38% dos tumores foram estadiados como T1a, 27,6% T1b, 24,1% T2 e 10,3% T3. Metástase linfonodal regional (N1) esteve presente em 44,8% dos casos. A presença de metástase a distância (M1) para o mediastino foi observada em um caso (3,4%). Variantes do proto-oncogene RET foram identificadas em 55,2% dos pacientes. A variante patogênica C634R foi identificada em um paciente (3,4%). Polimorfismos do RET foram identificados em 51,7% dos pacientes, sendo L769L o polimorfismo mais frequente. Discussão: RET C634R está associada ao diagnóstico de neoplasia endócrina múltipla tipo 2A, sendo descrita na literatura como a variante patogênica mais frequente (30-50%) entre os pacientes afetados. Conclusão: Este estudo descreveu, pela primeira vez, o perfil clínico e molecular de pacientes com carcinoma medular de tireoide na Bahia. Uma variante patogênica germinativa do RET foi identificada confirmando o diagnóstico de neoplasia endócrina múltipla tipo 2A em um paciente. Polimorfismos do proto-oncogene RET foram identificados em 51,7% dos pacientes.
publishDate 2023
dc.date.accessioned.fl_str_mv 2023-04-19T12:49:13Z
dc.date.available.fl_str_mv 2023-04-19T12:49:13Z
dc.date.issued.fl_str_mv 2023-02-27
dc.type.driver.fl_str_mv Mestrado Acadêmico
info:eu-repo/semantics/masterThesis
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
format masterThesis
status_str publishedVersion
dc.identifier.citation.fl_str_mv MATTA, Rafael Reis Campos da. Caracterização clínica e molecular de pacientes com carcinoma medular de tireoide do estado da Bahia. 84 f. il. Orientador: Helton Estrela Ramos. 2023. Dissertação (Mestrado) – Programa de Pós-Graduação em Processos Interativos dos Órgãos e Sistemas, Instituto de Ciências da Saúde, Universidade Federal da Bahia, Salvador.
dc.identifier.uri.fl_str_mv https://repositorio.ufba.br/handle/ri/36876
identifier_str_mv MATTA, Rafael Reis Campos da. Caracterização clínica e molecular de pacientes com carcinoma medular de tireoide do estado da Bahia. 84 f. il. Orientador: Helton Estrela Ramos. 2023. Dissertação (Mestrado) – Programa de Pós-Graduação em Processos Interativos dos Órgãos e Sistemas, Instituto de Ciências da Saúde, Universidade Federal da Bahia, Salvador.
url https://repositorio.ufba.br/handle/ri/36876
dc.language.iso.fl_str_mv por
language por
dc.relation.references.pt_BR.fl_str_mv 1. Deng Y, Li H, Wang M, Li N, Tian T, Wu Y, et al. Global burden of thyroid cancer from 1990 to 2017. JAMA Netw Open. 2020;3(6):e208759. doi: 10.1001/jamanet workopen.2020.8759 2. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-49. doi:10.3322/caac.21660 3. Instituto Nacional de Câncer José Alencar Gomes Da Silva. Estimativa 2020: incidência de câncer no Brasil. Rio de Janeiro: INCA; 2022. Disponível em: https://www.inca.gov.br/estimativa 4. World Health Organization. Classification of tumours. Endocrine tumours. Lyon: International Agency for Research on Cancer; 2022. Disponível em: https://tumourclassification.iarc.who.int/welcome/ 5. Czarniecka A, Oczko-Wojciechowska M, Hajduk A, Zeman M, Jarzab B. Current surgical management in RET mutation carriers. Endokrynol Pol. 2019;70(4):367-79. doi:10.5603/EP.a2019.0021 6. Kawai K, Takahashi M. Intracellular RET signaling pathways activated by GDNF. Cell Tissue Res. 2020;382(1):113-23. doi:10.1007/s00441-020-03262-1 7. Takahashi M, Ritz J, Cooper GM. Activation of a novel human transforming gene, ret, by DNA rearrangement. Cell. 1985;42(2):581-88. doi:10.1016/0092-8674(85)90115-1 8. Raue F, editor. Medullary thyroid carcinoma. Recent results cancer res. Cham: Springer International Publishing; 2015. 204 p. doi.org/10.1007/978-3-319-22542-5 9. Hofstra RM, Landsvater RM, Ceccherini I, Stulp RP, 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):375-6. doi: 10.1038/367375a0. 10. Kebebew E, Ituarte PH, Siperstein AE, Duh QY, Clark OH. Medullary thyroid carcinoma: clinical characteristics, treatment, prognostic factors, and a comparison of staging systems. Cancer. 2000;88(5):1139-48. doi: 10.1002/(sici)1097-0142(20000301)88:5<1139::aid-cncr26>3.0.co;2-z. 11. Romei C, Cosci B, Renzini G, Bottici V, Molinaro E, Agate L, et al. RET genetic screening of sporadic medullary thyroid cancer (MTC) allows the preclinical diagnosis of unsuspected gene carriers and the identification of a relevant percentage of hidden familial MTC (FMTC). Clin Endocrinol (Oxf). 2011;74(2):241-7. doi: 10.1111/j.1365-2265.2010.03900.x 12. Simbolo M, Mian C, Barollo S, Fassan M, Mafficini A, Neves D, et al. High-throughput mutation profiling improves diagnostic stratification of sporadic medullary thyroid carcinomas. Virchows Arch. 2014;465(1):73-8. doi: 10.1007/s00428-014-1589-3. 13. Wei S, LiVolsi VA, Montone KT, Morrissette JJ, Baloch ZW. Detection of Molecular Alterations in Medullary Thyroid Carcinoma Using Next-Generation Sequencing: an Institutional Experience. Endocr Pathol. 2016;27(4):359-362. doi: 10.1007/s12022-016-9446-3. 14. Romei C, Casella F, Tacito A, Bottici V, Valerio L, Viola D, et al. New insights in the molecular signature of advanced medullary thyroid cancer: evidence of a bad outcome of cases with double RET mutations. J Med Genet. 2016;53(11):729-734. doi: 10.1136/jmedgenet-2016-103833. 15. Hedayati M, Zarif Yeganeh M, Sheikholeslami S, Afsari F. Diversity of mutations in the RET proto-oncogene and its oncogenic mechanism in medullary thyroid cancer. Crit Rev Clin Lab Sci. 2016;53(4):217-27. doi: 10.3109/10408363.2015.1129529. 16. Qu N, Shi X, Zhao JJ, Guan H, Zhang TT, Wen SS, et al. Genomic and Transcriptomic Characterization of Sporadic Medullary Thyroid Carcinoma. Thyroid. 2020;30(7):1025-1036. doi: 10.1089/thy.2019.0531. 17. Kouvaraki MA, Shapiro SE, Perrier ND, Cote GJ, Gagel RF, Hoff AO, et al. RET proto-oncogene: a review and update of genotype-phenotype correlations in hereditary medullary thyroid cancer and associated endocrine tumors. Thyroid. 2005;15(6):531-44. doi: 10.1089/thy.2005.15.531. 18. Wells AS Junior, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015;25(6):567-10. doi:10.1089/thy.2014.0335 19. Chen H, Sippel RS, O'Dorisio MS, Vinick AI, Lloyd RV, Pacak K, et al. The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer. Pancreas. 2010;39(6):775-83. doi: 10.1097/ MPA.0b013e3181ebb4f0 20. Maia AL, Siqueira DR, Kulcsar MA, Tincani AJ, Mazeto GM, Maciel LM. Diagnosis, treatment, and follow-up of medullary thyroid carcinoma: recommendations by the Thyroid Department of the Brazilian Society of Endocrinology and Metabolism. Arch Endocrinol Metab. 2014;58(7):667-700. doi:10.1590/0004-2730000003427 21. Viola D, Elisei R. Management of Medullary Thyroid Cancer. Endocrinol Metab Clin North Am. 2019;48(1):285-301. doi:10.1016/j.ecl.2018.11.006 22. Randle RW, Balentine CJ, Leverson GE, Havlena JA, Sippel RS, Schneider DF, et al. Trends in the presentation, treatment, and survival of patients with medullary thyroid cancer over the past 30 years. Surgery. 2017;161(1):137-46. doi:10.1016/ j.surg.2016.04.053 23. Gilliland FD, Hunt WC, Morris DM, Key CR. Prognostic factors for thyroid carcinoma. A population-based study of 15,698 cases from the Surveillance, Epidemiology and End Results (SEER) program 1973-1991. Cancer. 1997;79(3):564-73. doi:10.1002/(sici)1097-0142(19970201)79:3<564::aid-cncr20>3.0.co;2-0 24. Kuo EJ, Sho S, Li N, Zanocco KA, Yeh MW, Livhits MJ. Risk Factors Associated With Reoperation and Disease-Specific Mortality in Patients With Medullary Thyroid Carcinoma. JAMA Surg. 2018;153(1):52-9. doi:10.1001/jamasurg.2017.3555 25. Miranda-Filho A, Lortet-Tieulent J, Bray F, et al. Thyroid cancer incidence trends by histology in 25 countries: a population-based study. Lancet Diabetes Endocrinol. 2021;9(4):225-234. doi:10.1016/S2213-8587(21)00027-9 26. Sierra MS, Soerjomataram I, Forman D. Thyroid cancer burden in Central and South America. Cancer Epidemiol. 2016;44 Suppl 1:S150-S157. doi:10.1016/j.canep.2016.07.017 27. Borges AKDM, Ferreira JD, Koifman S, Koifman RJ. Thyroid cancer in Brazil: a descriptive study of cases held on hospital-based cancer registries, 2000-2016. Epidemiol Serv Saude. 2020;29(4):e2019503. doi:10.5123/s1679-49742020000400012 28. Ceolin L, Duval MADS, Benini AF, Ferreira CV, Maia AL. Medullary thyroid carcinoma beyond surgery: advances, challenges, and perspectives. Endocr Relat Cancer. 2019;26(9):R499-R518. doi:10.1530/ERC-18-0574 29. Ball DW. Medullary thyroid cancer: monitoring and therapy. Endocrinol Metab Clin North Am. 2007;36(3):823-viii. doi:10.1016/j.ecl.2007.04.001 30. Sippel RS, Kunnimalaiyaan M, Chen H. Current management of medullary thyroid cancer. Oncologist. 2008;13(5):539-47. doi:10.1634/theoncologist.2007-0239 31. Roy M, Chen H, Sippel RS. Current understanding and management of medullary thyroid cancer. Oncologist. 2013;18(10):1093-100. doi:10.1634/theoncologist.2013-0053 32. Leboulleux S, Baudin E, Travagli JP, Schlumberger M. Medullary thyroid carcinoma. Clin Endocrinol (Oxf). 2004;61(3):299-310. doi:10.1111/j.1365-2265.2004.02037.x 33. Fussey JM, Vaidya B, Kim D, Clark J, Ellard S, Smith JA. The role of molecular genetics in the clinical management of sporadic medullary thyroid carcinoma: a systematic review. Clin Endocrinol (Oxf). 2019;91(6):697-707. doi:10.1111/cen.14060 34. Wells SA Jr, Pacini F, Robinson BG, Santoro M. Multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma: an update. J Clin Endocrinol Metab. 2013;98(8):3149-64. doi:10.1210/jc.2013-1204 35. Newey PJ. Multiple endocrine neoplasia. Medicine. 2021;49(9):539-43. doi.org/10.1016/j.mpmed.2021.06.003 36. Mathiesen JS, Effraimidis G, Rossing M, Rasmussen AK, Hoejberg L, Bastholt L, et al. Multiple endocrine neoplasia type 2: a review. Semin Cancer Biol. 2022;79:163-79. doi:10.1016/j.semcancer.2021.03.035 37. Raue F, Frank-Raue K. Update multiple endocrine neoplasia type 2. Fam Cancer. 2010;9(3):449-57. doi:10.1007/s10689-010-9320-2 38. Scapineli JO, Ceolin L, Puñales MK, Dora JM, Maia AL. MEN 2A-related cutaneous lichen amyloidosis: report of three kindred and systematic literature review of clinical, biochemical and molecular characteristics. Fam Cancer. 2016;15(4):625-33. doi:10.1007/s10689-016-9892-6 39. Coyle D, Friedmacher F, Puri P. The association between Hirschsprung's disease and multiple endocrine neoplasia type 2a: a systematic review. Pediatr Surg Int. 2014;30(8):751-6. doi:10.1007/s00383-014-3538-2 40. Castinetti F, Waguespack SG, Machens A, Uchino S, Hasse-Lazar K, Sando G, et al. Natural history, treatment, and long-term follow up of patients with multiple endocrine neoplasia type 2B: an international, multicentre, retrospective study. Lancet Diabetes Endocrinol. 2019;7(3):213-20. doi:10.1016/S2213-8587(18)30336-X 41. Hadoux J, Pacini F, Tuttle RM, Schlumberger M. Management of advanced medullary thyroid cancer. Lancet Diabetes Endocrinol. 2016;4(1):64-71. doi:10.1016/S2213-8587(15)00337-X 42. Niederle MB, Scheuba C, Riss P, Selberherr A, Koperek O, Niederle B. Early Diagnosis of Medullary Thyroid Cancer: Are Calcitonin Stimulation Tests Still Indicated in the Era of Highly Sensitive Calcitonin Immunoassays? Thyroid. 2020;30(7):974-984. doi: 10.1089/thy.2019.0785. 43. Park H, Park J, Choi MS, Kim J, Kim H, Shin JH, et al. Preoperative Serum Calcitonin and Its Correlation with Extent of Lymph Node Metastasis in Medullary Thyroid Carcinoma. Cancers (Basel). 2020;12(10):2894. doi: 10.3390/cancers12102894. 44. Turkdogan S, Forest VI, Hier MP, Tamilia M, Florea A, Payne RJ. Carcinoembryonic antigen levels correlated with advanced disease in medullary thyroid cancer. J Otolaryngol Head Neck Surg. 2018;47(1):55. doi:10.1186/s40463-018-0303-x 45. Pacini F, Castagna MG, Cipri C, Schumberger M. Medullary thyroid carcinoma. Clin Oncol (R Coll Radiol). 2010;22(6):475-85. doi:10.1016/j.clon.2010.05.002 46. Machens A, Ukkat J, Hauptmann S, Dralle H. Abnormal carcinoembryonic antigen levels and medullary thyroid cancer progression: a multivariate analysis. Arch Surg. 2007;142(3):289-94. doi:10.1001/archsurg.142.3.289 47. Buzdugă CM, Costea CF, Cărăuleanu A, Lozneanu L, Turliuc MD, Cucu AI, et al. Protean cytological, histological and immunohistochemical appearances of medullary thyroid carcinoma: current updates. Rom J Morphol Embryol. 2019;60(2):369-81. 48. Klöppel G. Tumour biology and histopathology of neuroendocrine tumours. Best Pract Res Clin Endocrinol Metab. 2007;21(1):15-31. doi:10.1016/j.beem.2007.01.004 49. Agarwal S, Bychkov A, Jung CK. Emerging Biomarkers in thyroid practice and research. Cancers (Basel). 2021;14(1):204. doi:10.3390/cancers14010204 50. Tisell LE, Oden A, Muth A, Altiparmak G, Mõlne J, Ahlman H, et al. The Ki67 index a prognostic marker in medullary thyroid carcinoma. Br J Cancer. 2003;89(11):2093-7. doi:10.1038/sj.bjc.6601453 51. Mian C, Pennelli G, Barollo S, Altiparmak G, Mõlne J, Ahlman H, et al. Combined RET and Ki-67 assessment in sporadic medullary thyroid carcinoma: a useful tool for patient risk stratification. Eur J Endocrinol. 2011;164(6):971-6. doi:10.1530/EJE-11-0079 52. Xu B, Fuchs TL, Ahmadi S, Alghamdi M, Alzumaili B, Mohamed-Amine B, et al. International medullary thyroid carcinoma grading system: a validated grading system for medullary thyroid carcinoma. J Clin Oncol. 2022;40(1):96-104. doi:10.1200/JCO.21.01329 53. Takahashi M. Structure and expression of the ret transforming gene. IARC Sci Publ. 1988;(92):189-97. 54. Avantaggiato V, Dathan NA, Grieco M, Fabien N, Lazzaro D, Fusco A, et al. Developmental expression of the RET protooncogene. Cell Growth Differ. 1994;5(3):305-11. 55. Schuchardt A, D'Agati V, Larsson-Blomberg L, Costantini F, Pachnis V. Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret. Nature. 1994;367(6461):380-83. doi:10.1038/367380a0 56. Ikeda I, Ishizaka Y, Tahira T, Suzuki T, Onda M, Sugimura T, et al. Specific expression of the ret proto-oncogene in human neuroblastoma cell lines. Oncogene. 1990;5(9):1291-6. 57. Santoro M, Rosati R, Grieco M, Berlingieri MT, D'Amato GL, Franciscis V de, et al. The ret proto-oncogene is consistently expressed in human pheochromocytomas and thyroid medullary carcinomas. Oncogene. 1990;5(10):1595-8. 58. Takahashi M, Buma Y, Taniguchi M. Identification of the ret proto-oncogene products in neuroblastoma and leukemia cells. Oncogene. 1991;6(2):297-301. 59. Pasini B, Hofstra RM, Yin L, et al. The physical map of the human RET proto-oncogene. Oncogene. 1995;11(9):1737-1743. 60. 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. 1988;3(5):571-8. 61. Iwamoto T, Taniguchi M, Asai N, Ohkusu K, Nakashima I, Takahashi M. cDNA cloning of mouse ret proto-oncogene and its sequence similarity to the cadherin superfamily. Oncogene. 1993;8(4):1087-91. 62. Sugaya R, Ishimaru S, Hosoya T, Saigo K, Emori Y. A Drosophila homolog of human proto-oncogene ret transiently expressed in embryonic neuronal precursor cells including neuroblasts and CNS cells. Mech Dev. 1994;45(2):139-45. doi:10.1016/0925-4773(94)90027-2 63. Marcos-Gutiérrez CV, Wilson SW, Holder N, Pachnis V. The zebrafish homologue of the ret receptor and its pattern of expression during embryogenesis. Oncogene. 1997;14(8):879-89. doi:10.1038/sj.onc.1201048 64. Hahn M, Bishop J. Expression pattern of Drosophila ret suggests a common ancestral origin between the metamorphosis precursors in insect endoderm and the vertebrate enteric neurons. Proc Natl Acad Sci USA. 2001;98(3):1053-8. doi: 10.1073/ pnas.98.3.1053 65. Machens A, Lorenz K, Dralle H. Constitutive RET tyrosine kinase activation in hereditary medullary thyroid cancer: clinical opportunities. J Intern Med. 2009;266(1):114-25. doi:10.1111/j.1365-2796.2009.02113.x 66. Phay JE, Shah MH. Targeting RET receptor tyrosine kinase activation in cancer. Clin Cancer Res. 2010;16(24):5936-41. doi:10.1158/1078-0432.CCR-09-0786 67. Anders J, Kjar S, Ibáñez CF. Molecular modeling of the extracellular domain of the RET receptor tyrosine kinase reveals multiple cadherin-like domains and a calcium-binding site. J Biol Chem. 2001;276(38):35808-17. doi:10.1074/jbc.M104968200 68. Mahato AK, Sidorova YA. RET receptor tyrosine kinase: role in neurodegeneration, obesity, and cancer. Int J Mol Sci. 2020;21(19):7108. doi:10.3390/ijms21197108 69. Ibáñez CF. Structure and physiology of the RET receptor tyrosine kinase. Cold Spring Harb Perspect Biol. 2013;5(2):a009134. doi:10.1101/cshperspect.a009134 70. Takahashi M, Asai N, Iwashita T, Isomura T, Miyazaki K, Matsuyama M. Characterization of the ret proto-oncogene products expressed in mouse L cells. Oncogene. 1993;8(11):2925-9. 71. Rochette L, Zeller M, Cottin Y, Vergely C. Insights into mechanisms of GDF15 and receptor gfral: therapeutic targets. Trends Endocrinol Metab. 2020;31(12):939-51. doi:10.1016/j.tem.2020.10.004 72. Tahira T, Ishizaka Y, Itoh F, Sugimura T, Nagao M. Characterization of ret proto-oncogene mRNAs encoding two isoforms of the protein product in a human neuroblastoma cell line. Oncogene. 1990;5(1):97-102. 73. Myers SM, Eng C, Ponder BA, Mulligan LM. Characterization of RET proto-oncogene 3' splicing variants and polyadenylation sites: a novel C-terminus for RET. Oncogene. 1995;11(10):2039-45. 74. Carter MT, Yome JL, Marcil MN, Martin CA, Vanhorne JB, Mulligan LM. Conservation of RET proto-oncogene splicing variants and implications for RET isoform function. Cytogenet Cell Genet. 2001;95(3-4):169-176. doi:10.1159/000059341 75. Pachnis V, Mankoo B, Costantini F. Expression of the c-ret proto-oncogene during mouse embryogenesis. Development. 1993;119(4):1005-17. doi:10.1242/dev.119.4.1005 76. Tsuzuki T, Takahashi M, Asai N, Iwashita T, Matsuyama M, Asai J. Spatial and temporal expression of the ret proto-oncogene product in embryonic, infant and adult rat tissues. Oncogene. 1995;10(1):191-8. 77. Trupp M, Belluardo N, Funakoshi H, Ibáñez CF. Complementary and overlapping expression of glial cell line-derived neurotrophic factor (GDNF), c-ret proto-oncogene, and GDNF receptor-alpha indicates multiple mechanisms of trophic actions in the adult rat CNS. J Neurosci. 1997;17(10):3554-67. doi:10.1523/JNEUROSCI.17-10-03554.1997 78. Bennett DL, Michael GJ, Ramachandran N, Munson JB, Averill S, Yan Q, et al. A distinct subgroup of small DRG cells express GDNF receptor components and GDNF is protective for these neurons after nerve injury. J Neurosci. 1998;18(8):3059-72. doi:10.1523/JNEUROSCI.18-08-03059.1998 79. Ichihara M, Murakumo Y, Takahashi M. RET and neuroendocrine tumors. Cancer Lett. 2004;204(2):197-211. doi:10.1016/S0304-3835(03)00456-7 80. Schuchardt A, D'Agati V, Pachnis V, Costantini F. Renal agenesis and hypodysplasia in ret-k- mutant mice result from defects in ureteric bud development. Development. 1996;122(6):1919-29. doi:10.1242/dev.122.6.1919 81. Chi X, Michos O, Shakya R, Riccio P, Enomoto H, Licht JD, et al. Ret-dependent cell rearrangements in the wolffian duct epithelium initiate ureteric bud morphogenesis. Dev Cell. 2009;17(2):199-209. doi:10.1016/j.devcel.2009.07.013 82. Davis TK, Hoshi M, Jain S. To bud or not to bud: the RET perspective in CAKUT. Pediatr Nephrol. 2014;29(4):597-608. doi:10.1007/s00467-013-2606-5 83. Meng X, Lindahl M, Hyvönen ME, Parvinen M, Rooij MD de, Hess MW, et al. Regulation of cell fate decision of undifferentiated spermatogonia by GDNF. Science. 2000;287(5457):1489-93. doi:10.1126/science.287.5457.1489 84. Naughton CK, Jain S, Strickland AM, Gupta A, Milbrandt J. Glial cell-line derived neurotrophic factor-mediated RET signaling regulates spermatogonial stem cell fate. Biol Reprod. 2006;74(2):314-21. doi:10.1095/biolreprod.105.047365 85. Jijiwa M, Kawai K, Fukihara J, Nakamura A, Hasegawa M, Suzuki C, et al. GDNF-mediated signaling via RET tyrosine 1062 is essential for maintenance of spermatogonial stem cells. Genes Cells. 2008;13(4):365-74. doi:10.1111/j.1365-2443.2008.01171. 86. Airaksinen MS, Saarma M. The GDNF family: signalling, biological functions and therapeutic value. Nat Rev Neurosci. 2002;3(5):383-94. doi:10.1038/nrn812 87. Accardo G, Conzo G, Esposito D, Gambardella C, Mazzella M, Castaldo F, et al. Genetics of medullary thyroid cancer: an overview. Int J Surg. 2017;41:(Suppl 1):S2-S6. doi:10.1016/j.ijsu.2017.02.064 88. Mulligan LM, Kwok JB, Healey CS, Elsdon MJ, Eng C, Gardner E, et al. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature. 1993;363(6428):458-60. doi:10.1038/363458a0 89. Donis-Keller H, Dou S, Chi D, Carlson KM, Toshima K, Lairmore, TC, et al. Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet. 1993;2(7):851-6. doi:10.1093/hmg/2.7.851 90. Li SY, Ding YQ, Si YL, Ye MJ, Xu CM, Qi XP. 5P Strategies for Management of Multiple Endocrine Neoplasia Type 2: A Paradigm of Precision Medicine. Front Endocrinol (Lausanne). 2020;11:543246. doi:10.3389/fendo.2020.543246 91. Raue F, Frank-Raue K. Genotype-phenotype correlation in multiple endocrine neoplasia type 2. Clinics (Sao Paulo). 2012;67(Suppl 1):69-75. doi: 10.6061 clinics/2012(sup01)13 92. Asai N, Iwashita T, Matsuyama M, Takahashi M. Mechanism of activation of the ret proto-oncogene by multiple endocrine neoplasia 2A mutations. Mol Cell Biol. 1995;15(3):1613-9. doi:10.1128/MCB.15.3.1613 93. Santoro M, Carlomagno F, Romano A, Bottaro DP, Dathan NA, Grieco M, et al. Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science. 1995;267(5196):381-3. doi:10.1126/science.7824936 94. Rothberg AE, Raymond VM, Gruber SB, Sisson J. Familial medullary thyroid carcinoma associated with cutaneous lichen amyloidosis. Thyroid. 2009;19(6):651-5. doi:10.1089/thy.2009.0021 95. Qi XP, Peng JZ, Yang XW, Cao Z-L, Yu X-H, Fang X-D, et al. The RET C611Y mutation causes MEN 2A and associated cutaneous. Endocr Connect. 2018;7(9):998-1005. doi:10.1530/EC-18-0220 96. Frank-Raue K, Rybicki LA, Erlic Z, Schweizer H, Winter A, Milos I, et al. Risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germline RET mutations located in exon 10. Hum Mutat. 2011;32(1):51-8. doi:10.0002/ humu.21385 97. Raue F, Frank-Raue K. Genotype-phenotype relationship in multiple endocrine neoplasia type 2. Implications for clinical management. Hormones (Athens). 2009;8(1):23-8. doi:10.14310/horm.2002.1218 98. Carlson KM, Dou S, Chi D, Scavarda N, Toshima K, Jackson CE, et al. Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B. Proc Natl Acad Sci USA. 1994;91(4):1579-83. doi:10.1073/pnas.91.4.1579 99. Smith DP, Houghton C, Ponder BA. Germline mutation of RET codon 883 in two cases of de novo MEN 2B. Oncogene. 1997;15(10):1213-17. doi:10.1038/sj.onc.1201481 100. Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF, 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(19):1575-9. doi:10.1001/jama.1996.03540190047028 101. Gimm O, Marsh DJ, Andrew SD, Frilling A, Dahia PL, Mulligan LM, et al. Germline dinucleotide mutation in codon 883 of the RET proto-oncogene in multiple endocrine neoplasia type 2B without codon 918 mutation. J Clin Endocrinol Metab. 1997;82(11):3902-4. doi:10.1210/jcem.82.11.4508 102. Mathiesen JS, Habra MA, Bassett JHD, Choudhury M, Balasubramanian SP, Howlett TA, et al. Risk profile of the RET A883F germline mutation: an international collaborative study. J Clin Endocrinol Metab. 2017;102(6):2069-74. doi:10.1210/jc.2016-3640 103. Songyang Z, Carraway KL 3rd, Eck MJ, Harrison SC, Feldman RA, Mohammadi M, et al. Catalytic specificity of protein-tyrosine kinases is critical for selective signalling. Nature. 1995;373(6514):536-9. doi:10.1038/373536a0 104. Gujral TS, Singh VK, Jia Z, Mulligan LM. Molecular mechanisms of RET receptor-mediated oncogenesis in multiple endocrine neoplasia 2B. Cancer Res. 2006;66(22):10741-9. doi:10.1158/0008-5472.CAN-06-3329 105. Knowles PP, Murray-Rust J, Kjaer S, Scott RP, Hanrahan S, Santoro M, et al. Structure and chemical inhibition of the RET tyrosine kinase domain. J Biol Chem. 2006;281(44):33577-87. doi: 10.1074/jbc. M605604200 106. Cranston AN, Carniti C, Oakhill K, Radzio-Andzelm E, Stone EA, McCallionet AS, al. RET is constitutively activated by novel tandem mutations that alter the active site resulting in multiple endocrine neoplasia type 2B. Cancer Res. 2006;66(20):10179-87. doi:10.1158/0008-5472.CAN-06-0884 107. Miyauchi A, Futami H, Hai N, Radzio-Andzelm E, Stone EA, McCallion AS, et al. Two germline missense mutations at codons 804 and 806 of the RET proto-oncogene in the same allele in a patient with multiple endocrine neoplasia type 2B without codon 918 mutation. Jpn J Cancer Res. 1999;90(1):1-5. doi:10.1111/j.1349-7006.1999.tb00658.x 108. Iwashita T, Murakami H, Kurokawa K, Kawai K, Miyauchi A, Futami H, et al. A two-hit model for development of multiple endocrine neoplasia type 2B by RET mutations. Biochem Biophys Res Commun. 2000;268(3):804-08. doi:10.1006/ bbrc.2000.2227 109. Kameyama K, Okinaga H, Takami H. RET oncogene mutations in 75 cases of familial medullary thyroid carcinoma in Japan. Biomed Pharmacother. 2004;58(6-7):345-7. doi:10.1016/j.biopha.2004.05.001 110. Nakao KT, Usui T, Ikeda M, Mori Y, Yamamoto T, Kawashima S-T, et al. Novel tandem germline RET proto-oncogene mutations in a patient with multiple endocrine neoplasia type 2B: report of a case and a literature review of tandem RET mutations with in silico analysis. Head Neck. 2013;35(12):E363-8. doi:10.1002/hed.23241 111. Mathew A, Latteyer S, Frank-Raue K, Moeller LC, Zwanziger D, Mengel M, et al. A Novel double RET E768D/L790F mutation associated with a MEN2B-Like phenotype. Thyroid. 2021;31(2):327-9. doi:10.1089/thy.2019.0472 112. Eng C, Mulligan LM, Healey CS, Houghton C, Frilling A, Raue F, et al. Heterogeneous mutation of the RET proto-oncogene in subpopulations of medullary thyroid carcinoma. Cancer Res. 1996;56(9):2167-70. 113. Eng C, Mulligan LM, Smith DP, Healey CS, Frilling A, Raue F, et al. Mutation of the RET protooncogene in sporadic medullary thyroid carcinoma. Genes Chromosomes Cancer. 1995;12(3):209-12. doi:10.1002/gcc.2870120308 114. Marsh DJ, Learoyd DL, Andrew SD, Krishnan L, Pojer R, Richardson AL, et al. Somatic mutations in the RET proto-oncogene in sporadic medullary thyroid carcinoma. Clin Endocrinol (Oxf). 1996;44(3):249-57. doi:10.1046/j.1365-2265.1996.681503.x 115. 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. doi:10.1210/jcem.81.4.8636377 116. Dvorakova S, Vaclavikova E, Sykorova V, Vcelak J, Novak Z, Duskova J, et al. Somatic mutations in the RET proto-oncogene in sporadic medullary thyroid carcinomas. Mol Cell Endocrinol. 2008;284(1-2):21-7. doi:10.1016/j.mce.2007.12.016 117. 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):682-7. doi:10.1210/jc.2007-1714 118. Moura MM, Cavaco BM, Pinto AE, Domingues R, Santos JR, Cid MO, et al. Correlation of RET somatic mutations with clinicopathological features in sporadic medullary thyroid carcinomas. Br J Cancer. 2009;100(11):1777-83. doi:10.1038/sj.bjc.6605056 119. Romei C, Ciampi R, Casella F, Tacito A, Torregrossa L, Ugolini C, et al. RET mutation heterogeneity in primary advanced medullary thyroid cancers and their metastases. Oncotarget. 2018;9(11):9875-84. doi:10.18632/oncotarget.23986 120. Mulligan LM, Marsh DJ, Robinson BG, Schuffenecker I, Zedenius J, Lips CJM, et al. Genotype-phenotype correlation in multiple endocrine neoplasia type 2: report of the International RET Mutation Consortium. J Intern Med. 1995;238(4):343-6. doi:10.1111/j.1365-2796.1995.tb01208.x 121. Machens A, Gimm O, Hinze R, Höppner W, Boehm BO, Dralle H. Genotype-phenotype correlations in hereditary medullary thyroid carcinoma: oncological features and biochemical properties. J Clin Endocrinol Metab. 2001;86(3):1104-9. doi:10.1210/jcem.86.3.7290 122. Yip L, Cote GJ, Shapiro SE, Ayers GD, Herzog CE, Sellin RV, et al. Multiple endocrine neoplasia type 2: evaluation of the genotype-phenotype relationship. Arch Surg. 2003;138(4):409-16. doi:10.1001/archsurg.138.4.409 123. Milos IN, Frank-Raue K, Wohllk N, Maia AL, Pusiol E, Patocs A, et al. Age-related neoplastic risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germ line RET Cys634Trp (TGC>TGG) mutation. Endocr Relat Cancer. 2008;15(4):1035-41. doi:10.1677/ERC-08-0105 124. Schuffenecker I, Virally-Monod M, Brohet R, Goldgar D, Conte-Devolx B, Leclerc L, et al. Risk and penetrance of primary hyperparathyroidism in multiple endocrine neoplasia type 2A families with mutations at codon 634 of the RET proto-oncogene. J Clin Endocrinol Metab. 1998;83(2):487-91. doi:10.1210/jcem.83.2.4529 125. Puñales MK, Graf H, Gross JL, Maia AL. RET codon 634 mutations in multiple endocrine neoplasia type 2: variable clinical features and clinical outcome. J Clin Endocrinol Metab. 2003;88(6):2644-9. doi:10.1210/jc.2002-021422 126. Jasim S, Ying AK, Waguespack SG, Rich TA, Grubbs EG, Jimenez C, et al. Multiple endocrine neoplasia type 2B with a RET proto-oncogene A883F mutation displays a more indolent form of medullary thyroid carcinoma compared with a RET M918T mutation. Thyroid. 2011;21(2):189-92. doi:10.1089/thy.2010.0328 127. Schilling T, Bürck J, Sinn HP, Clemens A. Prognostic value of codon 918 (ATG-->ACG) RET proto-oncogene mutations in sporadic medullary thyroid carcinoma. Int J Cancer. 2001;95(1):62-6. doi:10.1002/1097-0215(20010120)95:1<62::aid-ijc1011>3.0.co;2-1 128. Romei C, Ugolini C, Cosci B, Torregrossa L, Vivaldi A, Ciampi R, et al. Low prevalence of the somatic M918T RET mutation in micro-medullary thyroid cancer. Thyroid. 2012;22(5):476-81. doi:10.1089/thy.2011.0358 129. Raue F, Frank-Raue K. Update on multiple endocrine neoplasia type 2: focus on medullary thyroid carcinoma. J Endocr Soc. 2018;2(8):933-43.doi:10.1210/js.2018-00178 130. Lombardo F, Baudin E, Chiefari E, Arturi F, Bardet S, Caillou B, et al. Familial medullary thyroid carcinoma: clinical variability and low aggressiveness associated with RET mutation at codon 804. J Clin Endocrinol Metab. 2002;87(4):1674-80. doi:10.1210/jcem.87.4.8403 131. Lindskog S, Nilsson O, Jansson S, Illerskog A-C, Ysander L, Ahlman H, et al. Phenotypic expression of a family with multiple endocrine neoplasia type 2A due to a RET mutation at codon 618. Br J Surg. 2004;91(6):713-8. doi:10.1002/bjs.4457 132. Signorini PS, França MI, Camacho CP, Lindsey SC, Valente FOF, Kasamatsu TS, et al. A ten-year clinical update of a large RET p.Gly533Cys kindred with medullary thyroid carcinoma emphasizes the need for an individualized assessment of affected relatives. Clin Endocrinol (Oxf). 2014;80(2):235-45. doi:10.1111/cen.12264 133. Long KL, Etzel C, Rich T, et al. All in the family? Analyzing the impact of family history in addition to genotype on medullary thyroid carcinoma aggressiveness in MEN2A patients. Fam Cancer. 2017;16(2):283-9. doi:10.1007/s10689-016-9948-7 134. Machens A, Lorenz K, Weber F, Dralle H. Genotype-specific progression of hereditary medullary thyroid cancer. Hum Mutat. 2018;39(6):860-9. doi:10.1002/humu.
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