Медицинская литература. Новинки

 

 

 

 

 

 

Редкая герминальная мутация с.2752 A>G (p.M918V) в протоонкогене RET, выявленная у больного с метастазами медуллярного и папиллярного рака щитовидной железы в лимфатических узлах шеи

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У больного 62 лет, прооперированного в связи с рецидивом папиллярного рака щитовидной железы, в удаленных лимфоузлах клетчатки шеи были выявлены метастазы. Метастатическая опухолевая ткань была представлена папиллярной карциномой (ПКЩЖ) (фолликулярный вариант), перемешанной со значительно доминирующей иммунофенотипически отличной медуллярной карциномой щитовидной железы (МКЩЖ). С целью исключения наследственной МКЩЖ для пробанда был проведен сиквенс шести экзонов протоонкогена RET: 10, 11, 13-16 - с использованием геномной ДНК, выделенной из лимфоцитов периферической крови больного. В экзоне 16 неожиданно была выявлена редкая герминальная мутация с.2752 A>G (p.Met918Val) в одной из двух копий протоонкогена RET. Уровень кальцитонина через 4 мес после операции - 20 пг/мл при норме 2-6 пг/мл. У больного было исключено наличие феохромоцитомы и гиперпаратиреоза. При генетическом анализе родственников гетерозиготная замена с.2752 A>G обнаружена у здорового старшего сына пробанда (37 лет), но не найдена у его 96-летней матери и младшего сына. ДНК отца пробанда была недоступна. Мутация р.М918V отсутствует в хромосомах здоровых индивидов (n = 100). Представлено описание больного.

Ключевые слова:
щитовидная железа, медуллярная карцинома, папиллярная карцинома, синхронный (бинарный) рак, герминальная мутация, протоонкоген RET, thyroid, medullary carcinoma, papillary carcinoma, concurrent (associated) cancer, germline mutation, protooncogene RET

Литература:
1.1. Roman S, Lin R, Sosa JA. Prognosis of medullary thyroid carcinoma: demographic, clinical, and pathologic predictors of survival in 1252 cases. Cancer. 2006;107(9):2134-2142. doi: 10.1002/cncr.22244.
2.2. Kouvaraki MA, Shapiro SE, Perrier ND, 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):531-544. doi: 10.1089/thy.2005.15.531.
3.3. Eng C, Clayton D, Schuffenecker I, et al. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA.1996;276(19):1575-1579.
4.4. Elisei R, Cosci B, Romei C, 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. doi: 10.1210/jc.2007-1714.
5.5. Rosai J. Handling of thyroid follicular patterned lesions. Endocr Pathol. 2005;16(4):279-283.
6.6. Nose V. Familial non-medullary thyroid carcinoma: an update. Endocr Pathol. 2008;19(4):226-240. doi: 10.1007/s12022-008-9045-z.
7.7. DeLellis RA, Lloyd RV, Heitz PU, Eng C, editors. World Health Organization classification of tumours. Pathology and genetics of tumours of endocrine organs. Lyon: IARC Press; 2004. p. 92-93.
8.8. Rossi S, Fugazzola L, De Pasquale L, 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):281-289. doi: 10.1677/erc.1.00901.
9.9. Shifrin AL, Xenachis C, Fay A, et al. One hundred and seven family members with the rearranged during transfection V804M proto-oncogene mutation presenting with simultaneous medullary and papillary thyroid carcinomas, rare primary hyperparathyroidism, and no pheochromocytomas: is this a new syndrome - MEN 2C? Surgery. 2009;146(6):998-1005. doi: 10.1016/j.surg.2009.09.021.
10.10. Griffith C, Zhang S, Mukhopadhyay S. Synchronous metastatic medullary and papillary thyroid carcinomas in a patient with germline RET mutation: case report, molecular analysis, and implications for pathogenesis. Endocr Pathol.2010;21(2):115-119. doi: 10.1007/s12022-010-9117-8.
11.11. Costanzo M, Marziani A, Papa V, et al. Simultaneous medullary carcinoma and differentiated thyroid cancer. Case report. Ann Ital Chir. 2010;81(5):357-360.
12.12. Gul K, Ozdemir D, Ugras S, et al. Coexistent familial nonmultiple endocrine neoplasia medullary thyroid carcinoma and papillary thyroid carcinoma associated with RET polymorphism. Am J Med Sci. 2010;340(1):60-63. doi: 10.1097/MAJ.0b013e3181dfb245.
13.13. Sadat Alavi M, Azarpira N. Medullary and papillary carcinoma of the thyroid gland occurring as a collision tumor with lymph node metastasis: A case report. J Med Case Reports. 2011;5(1):590. doi: 10.1186/1752-1947-5-590.
14.14. Adnan Z, Arad E, Dana J, et al. Simultaneous occurrence of medullary and papillary thyroid microcarcinomas: a case series and review of the literature. J Med Case Rep. 2013;7:26. doi: 10.1186/1752-1947-7-26.
15.15. Brauckhoff M, Gimm O, Hinze R, et al. Papillary thyroid carcinoma in patients with RET proto-oncogene germline mutation. Thyroid. 2002;12(7):557-561. doi: 10.1089/105072502320288393.
16.16. Biscolla RP, Ugolini C, Sculli M, et al. Medullary and papillary tumors are frequently associated in the same thyroid gland without evidence of reciprocal influence in their biologic behavior. Thyroid. 2004;14(11):946-952. doi: 10.1089/thy.2004.14.946.
17.17. Kim WG, Gong G, Kim EY, et al. Concurrent occurrence of medullary thyroid carcinoma and papillary thyroid carcinoma in the same thyroid should be considered as coincidental. Clin Endocrinol (Oxf). 2010;72(2):256-263. doi: 10.1111/j.1365-2265.2009.03622.x.
18.18. Machens A, Dralle H. Simultaneous medullary and papillary thyroid cancer: a novel entity? Ann Surg Oncol. 2012;19(1):37-44. doi: 10.1245/s10434-011-1795-z.
19.19. Cupisti K, Raffel A, Ramp U, et al. Synchronous occurrence of a follicular, papillary and medullary thyroid carcinoma in a recurrent goiter. Endocr J. 2005;52(2):281-285.
20.20. Ergul E, Gozetlik EO. Does percutaneous thyroid laser ablation induce mixed papillary and medullary thyroid carcinoma? Acta Chir Belg. 2010;110(2):228-231.
21.21. Griniatsos J, Tsigris C, Kanakis M, et al. Increased incidence of papillary thyroid cancer detection among thyroidectomies in Greece between 1991 and 2006. Anticancer Res. 2009;29(12):5163-5169.
22.22. Калинин В.Н., Амосенко Ф.А., Пушкаш К., и др. Новая наследуемая мутация протоонкогена RET, ассоциированная с семейным медуллярным раком щитовидной железы, и полиморфизмы в окружающих областях. // Генетика. - 1998. - Т. 34. - №8 - С. 1157-1159.
23.23. Kalinin VN, Amosenko FA, Shabanov MA, et al. Three novel mutations in the RET proto-oncogene. J Mol Med (Berl). 2001;79(10):609-612. doi: 10.1007/s001090100250.
24.24. Амосенко Ф.А., Бржезовский В.В., Любченко Л.Н., и др. Анализ мутаций в протоонкогене RET у российских больных с медуллярным раком щитовидной железы. // Генетика. - 2003. - T. 39. - №6 - С. 847-854.
25.25. Ishida T, Kawai T, Iino Y, et al. Concurrent medullary carcinoma adjacent to papillary carcinoma of the thyroid - a clinicopathological and electron microscopic study. Gan No Rinsho. 1985;31(14): 1814-1820.
26.26. Apel RL, Alpert LC, Rizzo A, et al. A metastasizing composite carcinoma of the thyroid with distinct medullary and papillary components. Arch Pathol Lab Med. 1994;118(11):1143-1147.
27.27. Seki T, Kameyama K, Hayashi H, et al. Composite metastatic carcinoma in lymph nodes of patients with concurrent medullary and papillary thyroid carcinoma: a report of two cases. Endocr Pathol. 2004;15(1):83-88.
28.28. Papi G, Corrado S, Pomponi MG, et al. Concurrent lymph node metastases of medullary and papillary thyroid carcinoma in a case with RET oncogene germline mutation. Endocr Pathol. 2003;14(3):269-276.
29.29. Guyetant S, Dupre F, Bigorgne JC, et al. Medullary thyroid microcarcinoma: a clinicopathologic retrospective study of 38 patients with no prior familial disease. Hum Pathol. 1999;30(8):957-963.
30.30. Romei C, Mariotti S, Fugazzola L, et al. Multiple endocrine neoplasia type 2 syndromes (MEN 2): results from the ItaMEN network analysis on the prevalence of different genotypes and phenotypes. Eur J Endocrinol. 2010;163(2):301-308. doi: 10.1530/EJE-10-0333.
31.31. Cosci B, Vivaldi A, Romei C, et al. In silico and in vitro analysis of rare germline allelic variants of RET oncogene associated with medullary thyroid cancer. Endocr Relat Cancer. 2011;18(5): 603-612. doi: 10.1530/ERC-11-0117.
32.32. American Thyroid Association Guidelines Task Force; Kloos RT, Eng C, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009;19(6):565-612. doi: 10.1089/thy.2008.0403.
33.33. Brandi ML, Gagel RF, Angeli A, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab. 2001;86(12):5658-5671. doi: 10.1210/jcem.86.12.8070.
34.34. Iwashita T, Asai N, Murakami H, et al. Identification of tyrosine residues that are essential for transforming activity of the ret proto-oncogene with MEN2A or MEN2B mutation. Oncogene. 1996;12(3):481-487.
35.35. Hanks SK, Quinn AM, Hunter T. The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science. 1988;241(4861):42-52.
36.36. Hubbard SR. Crystal structure of the activated insulin receptor tyrosine kinase in complex with peptide substrate and ATP analog. EMBO J. 1997;16(18):5572-5581. doi: 10.1093/emboj/16.18.5572.
37.37. 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):10741-10749. doi: 10.1158/0008-5472.CAN-06-3329.
38.38. Dixit A, Torkamani A, Schork NJ, Verkhivker G. Computational modeling of structurally conserved cancer mutations in the RET and MET kinases: the impact on protein structure, dynamics, and stability. Biophys J. 2009;96(3):858-874.doi: 10.1016/j.bpj.2008.10.041.
39.39. Feldman GL, Edmonds MW, Ainsworth PJ, et al. Variable expressivity of familial medullary thyroid carcinoma (FMTC) due to a RET V804M (GTG-->ATG) mutation. Surgery. 2000;128(1):93-98. doi: 10.1067/msy.2000.107103.
40.40. Rey JM, Brouillet JP, Fonteneau-Allaire J, et al. Novel germline RET mutation segregating with papillary thyroid carcinomas. Genes Chromosomes Cancer. 2001;32(4):390-391.
41.41. Melillo RM, Cirafici AM, De Falco V, et al. The oncogenic activity of RET point mutants for follicular thyroid cells may account for the occurrence of papillary thyroid carcinoma in patients affected by familial medullary thyroid carcinoma. Am J Pathol. 2004;165(2):511-521. doi: 10.1016/S0002-9440(10)63316-0.
42.42. Niccoli-Sire P, Murat A, Rohmer V, et al. When should thyroidectomy be performed in familial medullary thyroid carcinoma gene carriers with non-cysteine RET mutations? Surgery. 2003;134(6):1029-1036; discussion 1036-1027. doi: 10.1016/j.surg.2003.07.019.
43.43. 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.
44.44. Ball DW. Medullary thyroid cancer: therapeutic targets and molecular markers. Curr Opin Oncol. 2007;19(1):18-23. doi: 10.1097/CCO.0b013e32801173ea.

A rare germline mutation c.2752 A>G (p.M918V) in the RET protooncogene in a patient with medullary and papillary thyroid carcinomas in cervical lymph node metastases: a case report and review of the literature

We report a rare germline RET mutation c.2752 A>G (p.M918V) found in a 62-year-old man with synchronous medullary thyroid carcinoma (MTC) and papillary thyroid carcinoma (PTC) (follicular variant) in cervical lymph node metastases with significant predominance of MTC. DNA sequencing of six exons (10, 11, 13-16) of the RET protooncogene from peripheral blood leucocytes was performed to exclude hereditary MTC in our patient. Postoperative CT was 20 pg/ml (N = 2-6 pg/ml). Pheochromocytoma and hyperparathyroidism were excluded. Genetic analysis of first-degree relatives showed that one of them, the healthy eldest son (37 y.o.), was a carrier of rare ATG>GTG heterozygous mutation at position c.2752 of the protooncogene RET. A 96-year-old mother of the patient and his younger son have not this mutation. The proband`s father was not available. The mutation was not revealed in 100 unrelated normal individuals. The clinical history is presented.

Keywords:
щитовидная железа, медуллярная карцинома, папиллярная карцинома, синхронный (бинарный) рак, герминальная мутация, протоонкоген RET, thyroid, medullary carcinoma, papillary carcinoma, concurrent (associated) cancer, germline mutation, protooncogene RET