Öz
Amaç: Multipl endokrin neoplazi tip 2 (MEN2), otozomal dominant kalıtım sergileyen bir sendrom
olup, germ hattında meydana gelen yanlış anlamlı RET proto-onkogen mutasyonları ile ilişkilendirilmiştir.
Mutasyon taşıyıcılarının yaklaşık %90’ının medüller tiroid karsinomu (MTK) geliştirdiği bilinmektedir.
Hastalarda RET mutasyon taraması ile genetik tanı sağlanmakta ve ailede henüz semptom
göstermeyen bireylerin mutasyon tipine göre önleyici cerrahi müdahaleye yönlendirilmeleri sağlanabilmektedir.
Bu bağlamda, çalışmamız sporadik MTK teşhisli bireyin klinik takiplerinin sağlanması ve
iki oğlu ile birlikte RET proto-onkogen genetik tanılarının gerçekleştirilmesini amaçlamıştır.
Yöntem: İndeks vakanın detaylı klinik değerlendirmeleri ile pre-operatuvar ve post-operatif histopatolojik
incelemeleri gerçekleştirilmiştir. Boyun ultrasonografisi ve biyokimyasal değerlendirmeler de
dahil olmak üzere rutin klinik takip yapılmıştır.
RET proto-onkogenin rutin genetik tanısı, genin 10, 11, 13-16’ıncı ekzonlarının PZR amplifikasyonunu
takiben Sanger dizilemesi yöntemleri ile gerçekleştirilmiştir. Mutasyon taşıyan ekzon hastanın
asemptomatik iki oğlunda taranmıştır.
Bulgular: İndeks vaka klinik incelemeler ve histopatolojik tanı ile sporadik MTK tanısı almıştır. RET
gen mutasyon taraması sonucunda hastanın 11. ekzonunda c.1891G>T (D631Y) mutasyonu ile 11 ve
13. ekzonlarında sırasıyla rs1799939 ve rs1800861 polimorfizmleri tespit edilmiştir. Hastanın her iki
oğlu da RET geni 11. ekzon için taranmış ancak mutasyon taşımadıkları bildirilmiştir.
Sonuç: Genetik tanı hem indeks vakanın sporadik MTK tanısını kesinleştirmiş hem de oğullarında
sağlıklı olduğunu göstermiştir. Bu çalışma, literatürde ilk defa feokromasitomaya eşlik etmeyen sporadik
medüller tiroid kanserli bir olguda D631Y mutasyon varlığını göstermektedir.
Anahtar Kelimeler
MEN2 Medüller tiroid karsinomu RET proto-onkogeni D631Y mutasyon
Kaynakça
- 1. Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF, van Amstel HKP, Lips CJ, Nishisho I, Takai SI, Marsh DJ, Robinson BG, Frank-Raue K, Raue F, Xue F, Noll WW, Romei C, Pacini F, Fink M, Niederle B, Zeden- ius J, Nordenskjold M, Komminoth P, Hendy GN, Gharib H, Thibodeau SN, Lacroix A, Frilling A, Ponder BAJ, Mulligan LM. The relationship between specific RET proto-oncogene mutations and disease pheno-type in multiple endocrine neoplasia type 2. International RET mutation consortium analysis JAMA. 1996; 276:1575-1579. 2. Pasquali D, Di Matteo FM, Renzullo A, Accardo G, Esposito D, Barbato F, Colantuoni V, Circelli L, Conzo G. Multiple endocrine neoplasia, the old and the new: a mini review. G. Chir 2012; 33(11–12): 370-373. 3. Donis-Keller H, Dou S, Chi D, Carlson KM, Toshima K, Lairmore TC, Howe JR, Moley JF, Goodfellow P, Wells SA. Mutations in the RET proto-oncogene are associated with MEN 2A and FMTK. Hum Mol Genet 1993; 2: 851–856. 4. Mulligan LM, Kwok JBJ, Healey CS, Elsdon MJ, Eng C, Gardner E, Love DR, Mole SE, Moore JK, Papi L, Ponder MA, Telenius H, Tunnacliffe A, Ponder BAJ. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature. 1993; 363: 458–460. 5. Brandi ML, Gagel RF, Angeli A, Bilezikian JP, Beck-Peccoz P, Bordi C, Conte-Devolx B, Falchetti A, Gheri RG, Libroia A, Lips CJ, Lombardi G, Mannelli M, Pacini F, Ponder BA, Raue F, Skogseid B, Tamburrano G, Thakker RV, Thompson NW, Tomassetti P, Tonelli F, Wells SA Jr, Marx SJ. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 2001; 86: 5658–5671. 6. Machens A, Dralle H. Familial prevalence and age of RET germline mutations: implications for screening. Clin Endocrinol (Oxf). 2008; 69:81-87. 7. Machens A, Holzhausen HJ, Thanh PN, Dralle H. Malignant progression from C-cell hyperplasia to medullary thyroid carcinoma in 167 carriers of RET germline mutations. Surgery 2003; 134:425-431. 8. Eng C. The RET proto-oncogene in multiple endocrine neoplasia type 2 and Hirschsprung’s disease. N Engl J Med 1996; 335: 943-951. 9. Kloos RT, Eng C, Evans DB, Francis GL, Gagel RF, Gharib H, Moley JF, Pacini F, Ringel MD, Schlumberger M, Wells SA Jr. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid 2009; 19: 565-612. 10. Elston MS, Meyer-Rochow GY, Holdaway I, Conaglen JV. Patients with RET D631Y Mutations Most Commonly Present with Pheochromocytoma and not Medullary Thyroid Carcinoma. Horm Metab Res 2012; 44: 339-342. 11. Accardo G, Conzo G, Esposito D, Gambardella C, Mazzella M, Castaldo F, Di Donna C, Polistena A, Avenia N, Colantuoni V, Giugliano D, Pasquali D. Genetics of medullary thyroid cancer: An overview. Int J Surg 2017; 41: S2- S6. 12. Fagin JA, Wells Jr. SA. Biologic and clinical perspectives on thyroid cancer. N Engl J Med 2016; 15(375): 1054-1067. 13. Lindsey SC, Kunii IS, Germano-Neto F, Sittoni MY, Camacho CP, Valente FO, Yang JH, Signorini PS, Delcelo R, Cerutti JM, Maciel RM, Dias-da-Silva MR. Extended RET gene analysis in patients with apparently sporadic medullary thyroid cancer: clinical benefits and cost. Horm Cancer 2012; 3(4):181-186. 14. Santos MA, Quedas EP, Toledo Rde A, Lourenço DM Jr, Toledo SP. Screening of RET gene mutations in multiple endocrine neoplasia type-2 using conformation sensitive gel electrophoresis (CSGE). Arq Bras Endocrinol Metabol 2007; 51(9): 1468-1476. 15. Zupan A, Glavač D. “he development of rapid and accurate screening test for RET hotspot somatic and germline mutations in MEN2 syndromes. Exp Mol Pathol 2015; 99: 416-425. 16. Castinetti F, Moley J, Mulligan LM, Waguespack SG. A Comprehensive Review On MEN2B. Endocr Relat Cancer 2017; ERC-17- 0209. 17. Moline J ve Eng C. Multiple endocrine neoplasia type 2: An overview. Genet Med 2011; 13: 755-764. 18. Fugazzola L, Muzza M, Mian C, Cordella D, Barollo S, Alberti L, Cirello V, Dazzi D, Girelli ME, Opocher G, Beck-Peccoz P, Persani L. RET genotypes in sporadic medullary thyroid cancer: studies in a large Italian series. Clin Endocrinol Oxf 2008; 69:418-425. 19. Bae SJ, Kim D-J, Kim JY, Park SY, Choi SH, Song YD, Ki C-S, Jae Hoon Chung JH. A Rare Extracellular D631Y Germline Mutation of the RET Proto-Oncogene in Two Korean Families with Multiple Endocrine Neoplasia 2A. Thyroid 2006; 16(6): 609-614.
Öz
Objectives: Multiple endocrine neoplasia type 2 (MEN2) syndrome is associated with germ-line
missense mutations in RET proto-oncogene, inherited in an autosomal dominant manner. Approximately
90% of RET mutations were shown to develop medullary thyroid carcinoma (MTK). Genetic
testing is accomplished through RET mutation screen and asymptomatic first degree relatives of index
cases are recommended to be tested for preventative surgical operations. Thus, we aimed to perform
clinical follow-up of a sporadic MTK case, as well as to carry out RET proto-oncogen genetic diagnosis
on the index case and her two sons.
Materials and Methods: Index case has been subjected to detailed clinical evaluations, as well as
to pre- and post-operative hystopathological examinations. Routine clinical follow-up including neck
ultrasonography and biochemical evaluations have been performed. RET proto-oncogene routine
diag-nostic test was performed on 10, 11, 13-16th exons of the gene through PCR-amplification
followed by Sanger sequencing. Exon with a mutation was screened on index cases’ two sons.
Results: Clinical evaluations diagnosed index case as MTK. RET genetic screen revealed c.1891G>T
(D631Y) in 11th exon confirming diagnosis. The two sons were found negative for RET gene mutations
in their 11th exons.
Conclusion: Genetic diagnosis both confirmed clinical diagnosis of the index case and showed that
the sons are healthy. This is the first report of a D631Y mutation in a case of sporadic medullary thyroid
cancer without pheochromocytoma in the literature.
Anahtar Kelimeler
MEN2 Medullary thyroid carcinoma RET proto-oncogene D631Y mutation
Kaynakça
- 1. Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF, van Amstel HKP, Lips CJ, Nishisho I, Takai SI, Marsh DJ, Robinson BG, Frank-Raue K, Raue F, Xue F, Noll WW, Romei C, Pacini F, Fink M, Niederle B, Zeden- ius J, Nordenskjold M, Komminoth P, Hendy GN, Gharib H, Thibodeau SN, Lacroix A, Frilling A, Ponder BAJ, Mulligan LM. The relationship between specific RET proto-oncogene mutations and disease pheno-type in multiple endocrine neoplasia type 2. International RET mutation consortium analysis JAMA. 1996; 276:1575-1579. 2. Pasquali D, Di Matteo FM, Renzullo A, Accardo G, Esposito D, Barbato F, Colantuoni V, Circelli L, Conzo G. Multiple endocrine neoplasia, the old and the new: a mini review. G. Chir 2012; 33(11–12): 370-373. 3. Donis-Keller H, Dou S, Chi D, Carlson KM, Toshima K, Lairmore TC, Howe JR, Moley JF, Goodfellow P, Wells SA. Mutations in the RET proto-oncogene are associated with MEN 2A and FMTK. Hum Mol Genet 1993; 2: 851–856. 4. Mulligan LM, Kwok JBJ, Healey CS, Elsdon MJ, Eng C, Gardner E, Love DR, Mole SE, Moore JK, Papi L, Ponder MA, Telenius H, Tunnacliffe A, Ponder BAJ. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature. 1993; 363: 458–460. 5. Brandi ML, Gagel RF, Angeli A, Bilezikian JP, Beck-Peccoz P, Bordi C, Conte-Devolx B, Falchetti A, Gheri RG, Libroia A, Lips CJ, Lombardi G, Mannelli M, Pacini F, Ponder BA, Raue F, Skogseid B, Tamburrano G, Thakker RV, Thompson NW, Tomassetti P, Tonelli F, Wells SA Jr, Marx SJ. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 2001; 86: 5658–5671. 6. Machens A, Dralle H. Familial prevalence and age of RET germline mutations: implications for screening. Clin Endocrinol (Oxf). 2008; 69:81-87. 7. Machens A, Holzhausen HJ, Thanh PN, Dralle H. Malignant progression from C-cell hyperplasia to medullary thyroid carcinoma in 167 carriers of RET germline mutations. Surgery 2003; 134:425-431. 8. Eng C. The RET proto-oncogene in multiple endocrine neoplasia type 2 and Hirschsprung’s disease. N Engl J Med 1996; 335: 943-951. 9. Kloos RT, Eng C, Evans DB, Francis GL, Gagel RF, Gharib H, Moley JF, Pacini F, Ringel MD, Schlumberger M, Wells SA Jr. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid 2009; 19: 565-612. 10. Elston MS, Meyer-Rochow GY, Holdaway I, Conaglen JV. Patients with RET D631Y Mutations Most Commonly Present with Pheochromocytoma and not Medullary Thyroid Carcinoma. Horm Metab Res 2012; 44: 339-342. 11. Accardo G, Conzo G, Esposito D, Gambardella C, Mazzella M, Castaldo F, Di Donna C, Polistena A, Avenia N, Colantuoni V, Giugliano D, Pasquali D. Genetics of medullary thyroid cancer: An overview. Int J Surg 2017; 41: S2- S6. 12. Fagin JA, Wells Jr. SA. Biologic and clinical perspectives on thyroid cancer. N Engl J Med 2016; 15(375): 1054-1067. 13. Lindsey SC, Kunii IS, Germano-Neto F, Sittoni MY, Camacho CP, Valente FO, Yang JH, Signorini PS, Delcelo R, Cerutti JM, Maciel RM, Dias-da-Silva MR. Extended RET gene analysis in patients with apparently sporadic medullary thyroid cancer: clinical benefits and cost. Horm Cancer 2012; 3(4):181-186. 14. Santos MA, Quedas EP, Toledo Rde A, Lourenço DM Jr, Toledo SP. Screening of RET gene mutations in multiple endocrine neoplasia type-2 using conformation sensitive gel electrophoresis (CSGE). Arq Bras Endocrinol Metabol 2007; 51(9): 1468-1476. 15. Zupan A, Glavač D. “he development of rapid and accurate screening test for RET hotspot somatic and germline mutations in MEN2 syndromes. Exp Mol Pathol 2015; 99: 416-425. 16. Castinetti F, Moley J, Mulligan LM, Waguespack SG. A Comprehensive Review On MEN2B. Endocr Relat Cancer 2017; ERC-17- 0209. 17. Moline J ve Eng C. Multiple endocrine neoplasia type 2: An overview. Genet Med 2011; 13: 755-764. 18. Fugazzola L, Muzza M, Mian C, Cordella D, Barollo S, Alberti L, Cirello V, Dazzi D, Girelli ME, Opocher G, Beck-Peccoz P, Persani L. RET genotypes in sporadic medullary thyroid cancer: studies in a large Italian series. Clin Endocrinol Oxf 2008; 69:418-425. 19. Bae SJ, Kim D-J, Kim JY, Park SY, Choi SH, Song YD, Ki C-S, Jae Hoon Chung JH. A Rare Extracellular D631Y Germline Mutation of the RET Proto-Oncogene in Two Korean Families with Multiple Endocrine Neoplasia 2A. Thyroid 2006; 16(6): 609-614.
Ayrıntılar
| Bölüm | Makale |
|---|---|
| Yazarlar | |
| Yayımlanma Tarihi | 1 Haziran 2017 |
| Yayımlandığı Sayı | Yıl 2017 Cilt: 7 Sayı: 13 |
