甲状腺癌分子生物学研究进展_West China Medical Journal

Authors：

 彭茜 ,  安振梅

四川大学华西医院内分泌与代谢病学科（成都，610041）;

Corresponding author：

安振梅, Email: anzm1997@sina.com

Keywords：

甲状腺癌; 基因突变; 分子靶向治疗

DOI：

10.7507/1002-0179.20140113

Video：

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甲状腺癌是内分泌系统最常见的肿瘤，且各国甲状腺癌发病率不断上升。依据不同的组织学和临床特征，滤泡细胞来源的甲状腺癌分为高分化癌（包括乳头状癌、滤泡状癌）和未分化癌。另有起源于滤泡旁降钙素分泌细胞的甲状腺髓样癌。随着分子生物学的发展，与甲状腺癌有关的基因突变不断被人们所认识。近年来，分子靶向治疗成为研究热点，多种治疗甲状腺癌的分子靶向药物进入临床试验阶段，为甲状腺癌尤其是难治性甲状腺癌的治疗带来希望。现就甲状腺癌的分子生物学研究进展作一综述。

Citation： 彭茜, 安振梅. 甲状腺癌分子生物学研究进展. West China Medical Journal, 2014, 29(2): 368-372. doi: 10.7507/1002-0179.20140113 Copy

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2.	Siraj AK,Hussain AR,Al-Rasheed M,et al.Demethylation of TMS1 gene sensitizes thyroid cancer cells to TRAIL-induced apoptosis[J].Clin Endocrinol Metab,2011,96(1):E215-E224.
3.	Enewold L,Zhu K,Ron E,et al.Rising thyroid cancer incidence in the United States by demographic and tumor characteristics,1980-2005[J].Cancer Epidemiol Biomarkers Prev,2009,18(3):784-791.
4.	Kilfoy BA,Zheng T,Holford TR,et al.International patterns and trends in thyroid cancer incidence,1973-2002[J].Cancer Causes Control,2009,20(5):525-531.
5.	Hogan AR,Zhuge Y,Perez EA,et al.Pediatric thyroid carcinoma:incidence and outcomes in 1753 patients[J].J Surg Res,2009,156(1):167-172.
6.	Alston RD,Geraci M,Eden TO,et al.Changes in cancer incidence in teenagers and young adults (ages 13 to 24 years) in England[J].Cancer,2008,113(10):2807-2815.
7.	Steliarova-Foucher E,Stiller CA,Pukkala E,et al.Thyroid cancer incidence and survival among European children and adolescents (1978-1997):report from the Automated Childhood Cancer Information System project[J].Eur J Cancer,2006,42(13):2150-2169.
8.	Xiang J,Wu Y,Li DS,et al.New clinical features of thyroid cancer in eastern China[J].J Visc Surg,2010,147(1):e53-e56.
9.	Elashoff M,Matveyenko AV,Gier B,et al.Pancreatitis,pancreatic,and thyroid cancer with glucagon-like peptide-1-based therapies[J].Gastroenterology,2011,141(1):150-156.
10.	Neta G,Brenner AV,Sturgis EM,et al.Common genetic variants related to genomic integrity and risk of papillary thyroid cancer[J].Carcinogenesis,2011,32(8):1231-1237.
11.	American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer,Cooper DS,Doherty GM,et al.Revised American thyroid association management guidelines for patients with thyroid nodules and differentiated thyroid cancer[J].Thyroid,2009,19(11):1167-1214.
12.	Yau T,Lo CY,Epstein RJ,et al.Treatment outcomes in anaplastic thyroid carcinoma:survival improvement in young patients with localized disease treated by combination of surgery and radiotherapy[J].Ann Surg Oncol,2008,15(9):2500-2505.
13.	Schlumberger M,Carlomagno F,Baudin E,et al.New therapeutic approaches to treat medullary thyroid carcinoma[J].Nat Clin Pract Endocrinol Metab,2008,4(1):22-32.
14.	Henderson YC,Shellenberger TD,Williams MD,et al.High rate of BRAF and RET/PTC dual mutations associated with recurrent papillary thyroid carcinoma[J].Clin Cancer Res,2009,15(2):485-491.
15.	Elisei R,Ugolini C,Viola D,et al.BRAF (V600E) mutation and outcome of patients with papillary thyroid carcinoma:a 15-year median follow-up study[J].J Clin Endocrinol Metab,2008,93(10):3943-3949.
16.	Kim TH,Park YJ,Lim JA,et al.The association of the BRAF (V600E) mutation with prognostic factors and poor clinical outcome in papillary thyroid cancer:a meta-analysis[J].Cancer,2012,118(7):1764-1773.
17.	Howell GM,Carty SE,Armstrong MJ,et al.Both BRAF V600E mutation and older age (≥65 years) are associated with recurrent papillary thyroid cancer[J].Ann Surg Oncol,2011,18(13):3566-3571.
18.	Riesco-Eizaguirre G,Gutiérrez-Martínez P,García-Cabezas MA,et al.The oncogene BRAF V600E is associated with a high risk of recurrence and less differentiated papillary thyroid carcinoma due to the impairment of Na+/I-targeting to the membrane[J].Endocr Relat Cancer,2006,13(1):257-269.
19.	Nikiforov YE,Ohori NP,Hodak SP,et al.Impact of mutational testing on the diagnosis and management of patients with cytologically indeterminate thyroid nodules:a prospective analysis of 1056 FNA samples[J].J Clin Endocrinol Metab,2011,96(11):3390-3397.
20.	Nikiforova MN,Nikiforov YE.Molecular diagnostics and predictors in thyroid cancer[J].Thyroid,2009,19(12):1351-1361.
21.	Nikiforov Y,Nikiforova MN.Molecular genetics and diagnosis of thyroid cancer[J].Nat Rev Endocrinol,2011,7(10):569-580.
22.	Gandhi M,Evdokimova V,Nikiforov YE.Mechanisms of chromosomal rearrangements in solid tumors:the model of papillary thyroid carcinoma[J].Mol Cell Endocrinol,2010,321(1):36-43.
23.	Hamatani K,Eguchi H,Ito R,et al.RET/PTC rearrangements preferentially occurred in papillary thyroid cancer among atomic bomb survivors exposed to high radiation dose[J].Cancer Res,2008,68(17):7176-7182.
24.	Ameziane-El-Hassani R,Boufraqech M,Lagente-Chevallier O,et al.Role of H₂O₂ in RET/PTC1 chromosomal rearrangement produced by ionizing radiation in human thyroid cells[J].Cancer Res,2010,70(10):4123-4132.
25.	Wang YL,Zhang RM,Luo ZW,et al.High frequency of level Ⅱ-V lymph node involvement in RET/PTC positive papillary thyroid carcinoma[J].Eur J Surg Oncol,2008,34(1):77-81.
26.	Cyniak-Magierska A,Brzeziańska E,Januszkiewicz-Caulier J,et al.Prevalence of RAS point mutations in papillary thyroid carcinoma;a novel mutation at codon 31 of K-RAS[J].Exp Clin Endocrinol Diabetes,2007,115(9):594-599.
27.	Sadow PM,Heinrich MC,Corless CL,et al.Absence of BRAF,NRAS,KRAS,HRAS mutations,and RET/PTC gene rearrangements distinguishes dominant nodules in Hashimoto thyroiditis from papillary thyroid carcinomas[J].Endocr Pathol,2010,21(2):73-79.
28.	Fukahori M,Yoshida A,Hayashi H,et al.The associations between RAS mutations and clinical characteristics in follicular thyroid tumors:new insights from a single center and a large patient cohort[J].Thyroid,2012,22(7):683-689.
29.	Rivera M,Ricarte-Filho J,Knauf J,et al.Molecular genotyping of papillary thyroid carcinoma follicular variant according to its histological subtypes (encapsulated vs infiltrative) reveals distinct BRAF and RAS mutation patterns[J].Mod Pathol,2010,23(9):1191-1200.
30.	Kroll TG,Sarraf P,Pecciarini L,et al.PAX8-PPAR gamma1 fusion oncogene in human thyroid carcinoma[corrected[J].Science,2000,289(5483):1357-1360.
31.	Gregory Powell J,Wang X,Allard BL,et al.The PAX8/PPAR gamma fusion oncoprotein transforms immortalized human thyrocytes through a mechanism probably involving wild-type PPARgamma inhibition[J].Oncogene,2004,23(20):3634-3641.
32.	Castro P,Rebocho AP,Soares RJ,et al.PAX8-PPARgamma rearrangement is frequently detected in the follicular variant of papillary thyroid carcinoma[J].J Clin Endocrinol Metab,2006,91(1):213-220.
33.	Adeniran AJ,Zhu Z,Gandhi M,et al.Correlation between genetic alterations and microscopic features,clinical manifestations,and prognostic characteristics of thyroid papillary carcinomas[J].Am J Surg Pathol,2006,30(2):216-222.
34.	Ohori NP,Nikiforova MN,Schoedel KE,et al.Contribution of molecular testing to thyroid fine-needle aspiration cytology of "follicular lesion of undetermined significance/atypia of undetermined significance"[J].Cancer Cytopathol,2010,118(1):17-23.
35.	Schlumberger MJ,Elisei R,Bastholt L,et al.Phase Ⅱ study of safety and efficacy of motesanib in patients with progressive or symptomatic,advanced or metastatic medullary thyroid cancer[J].J Clin Oncol,2009,27(23):3794-3801.
36.	Kloos RT,Ringel MD,Knopp MV,et al.Phase Ⅱ trial of sorafenib in metastatic thyroid cancer[J].J Clin Oncol,2009,27(10):1675-1684.
37.	Ravaud A,de LC,Courbon F,et al.Sunitinib in patients with refractory advanced thyroid cancer:the THYSU phase Ⅱ tria[J].Oncologist,2010,15(2):212-213.
38.	Carr L,Goulart B,Martins R,et al.Phase Ⅱ trial of continuous dosing of sunitinib in advanced,FDG-PET avid,medullary thyroid carcinoma (MTC) and well-differentiated thyroid cancer (WDTC)[J].J Clin Oncol,2009,27(15):6056.
39.	Wells JS,Gosnell J,Gagel R,et al.Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer[J].J Clin Oncol,2010,28(5):767-772.
40.	Wells SA,Robinson BG,Gagel RF,et al.Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer:a randomized,double-blind phaseⅢ trial[J].J Clin Oncol,2012,30(2):134-141.
41.	Flaherty K,Puzanov I,Sosman J,et al.Phase I study of PLX4032:proof of concept for V600E BRAF mutation as a therapeutictargetin human cancer[J].J Clin Oncol (Meeting Abstracts),2009,27(Suppl):9000.
42.	Schwartz GK,Robertson S,Shen A,et al.A phase I study of XL281,a selective oral RAF kinase inhibitor,in patients (Pts) with advanced solid tumors[J].J Clin Onco l (Meeting Abstracts),2009,27(Suppl):3513.

1. Sonkar AA,Rajamanickam S,Singh D.Papillary thyroid carcinoma:debate at rest[J].Indian J Cancer,2010,47(2):206-216.
2. Siraj AK,Hussain AR,Al-Rasheed M,et al.Demethylation of TMS1 gene sensitizes thyroid cancer cells to TRAIL-induced apoptosis[J].Clin Endocrinol Metab,2011,96(1):E215-E224.
3. Enewold L,Zhu K,Ron E,et al.Rising thyroid cancer incidence in the United States by demographic and tumor characteristics,1980-2005[J].Cancer Epidemiol Biomarkers Prev,2009,18(3):784-791.
4. Kilfoy BA,Zheng T,Holford TR,et al.International patterns and trends in thyroid cancer incidence,1973-2002[J].Cancer Causes Control,2009,20(5):525-531.
5. Hogan AR,Zhuge Y,Perez EA,et al.Pediatric thyroid carcinoma:incidence and outcomes in 1753 patients[J].J Surg Res,2009,156(1):167-172.
6. Alston RD,Geraci M,Eden TO,et al.Changes in cancer incidence in teenagers and young adults (ages 13 to 24 years) in England[J].Cancer,2008,113(10):2807-2815.
7. Steliarova-Foucher E,Stiller CA,Pukkala E,et al.Thyroid cancer incidence and survival among European children and adolescents (1978-1997):report from the Automated Childhood Cancer Information System project[J].Eur J Cancer,2006,42(13):2150-2169.
8. Xiang J,Wu Y,Li DS,et al.New clinical features of thyroid cancer in eastern China[J].J Visc Surg,2010,147(1):e53-e56.
9. Elashoff M,Matveyenko AV,Gier B,et al.Pancreatitis,pancreatic,and thyroid cancer with glucagon-like peptide-1-based therapies[J].Gastroenterology,2011,141(1):150-156.
10. Neta G,Brenner AV,Sturgis EM,et al.Common genetic variants related to genomic integrity and risk of papillary thyroid cancer[J].Carcinogenesis,2011,32(8):1231-1237.
11. American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer,Cooper DS,Doherty GM,et al.Revised American thyroid association management guidelines for patients with thyroid nodules and differentiated thyroid cancer[J].Thyroid,2009,19(11):1167-1214.
12. Yau T,Lo CY,Epstein RJ,et al.Treatment outcomes in anaplastic thyroid carcinoma:survival improvement in young patients with localized disease treated by combination of surgery and radiotherapy[J].Ann Surg Oncol,2008,15(9):2500-2505.
13. Schlumberger M,Carlomagno F,Baudin E,et al.New therapeutic approaches to treat medullary thyroid carcinoma[J].Nat Clin Pract Endocrinol Metab,2008,4(1):22-32.
14. Henderson YC,Shellenberger TD,Williams MD,et al.High rate of BRAF and RET/PTC dual mutations associated with recurrent papillary thyroid carcinoma[J].Clin Cancer Res,2009,15(2):485-491.
15. Elisei R,Ugolini C,Viola D,et al.BRAF (V600E) mutation and outcome of patients with papillary thyroid carcinoma:a 15-year median follow-up study[J].J Clin Endocrinol Metab,2008,93(10):3943-3949.
16. Kim TH,Park YJ,Lim JA,et al.The association of the BRAF (V600E) mutation with prognostic factors and poor clinical outcome in papillary thyroid cancer:a meta-analysis[J].Cancer,2012,118(7):1764-1773.
17. Howell GM,Carty SE,Armstrong MJ,et al.Both BRAF V600E mutation and older age (≥65 years) are associated with recurrent papillary thyroid cancer[J].Ann Surg Oncol,2011,18(13):3566-3571.
18. Riesco-Eizaguirre G,Gutiérrez-Martínez P,García-Cabezas MA,et al.The oncogene BRAF V600E is associated with a high risk of recurrence and less differentiated papillary thyroid carcinoma due to the impairment of Na+/I-targeting to the membrane[J].Endocr Relat Cancer,2006,13(1):257-269.
19. Nikiforov YE,Ohori NP,Hodak SP,et al.Impact of mutational testing on the diagnosis and management of patients with cytologically indeterminate thyroid nodules:a prospective analysis of 1056 FNA samples[J].J Clin Endocrinol Metab,2011,96(11):3390-3397.
20. Nikiforova MN,Nikiforov YE.Molecular diagnostics and predictors in thyroid cancer[J].Thyroid,2009,19(12):1351-1361.
21. Nikiforov Y,Nikiforova MN.Molecular genetics and diagnosis of thyroid cancer[J].Nat Rev Endocrinol,2011,7(10):569-580.
22. Gandhi M,Evdokimova V,Nikiforov YE.Mechanisms of chromosomal rearrangements in solid tumors:the model of papillary thyroid carcinoma[J].Mol Cell Endocrinol,2010,321(1):36-43.
23. Hamatani K,Eguchi H,Ito R,et al.RET/PTC rearrangements preferentially occurred in papillary thyroid cancer among atomic bomb survivors exposed to high radiation dose[J].Cancer Res,2008,68(17):7176-7182.
24. Ameziane-El-Hassani R,Boufraqech M,Lagente-Chevallier O,et al.Role of H₂O₂ in RET/PTC1 chromosomal rearrangement produced by ionizing radiation in human thyroid cells[J].Cancer Res,2010,70(10):4123-4132.
25. Wang YL,Zhang RM,Luo ZW,et al.High frequency of level Ⅱ-V lymph node involvement in RET/PTC positive papillary thyroid carcinoma[J].Eur J Surg Oncol,2008,34(1):77-81.
26. Cyniak-Magierska A,Brzeziańska E,Januszkiewicz-Caulier J,et al.Prevalence of RAS point mutations in papillary thyroid carcinoma;a novel mutation at codon 31 of K-RAS[J].Exp Clin Endocrinol Diabetes,2007,115(9):594-599.
27. Sadow PM,Heinrich MC,Corless CL,et al.Absence of BRAF,NRAS,KRAS,HRAS mutations,and RET/PTC gene rearrangements distinguishes dominant nodules in Hashimoto thyroiditis from papillary thyroid carcinomas[J].Endocr Pathol,2010,21(2):73-79.
28. Fukahori M,Yoshida A,Hayashi H,et al.The associations between RAS mutations and clinical characteristics in follicular thyroid tumors:new insights from a single center and a large patient cohort[J].Thyroid,2012,22(7):683-689.
29. Rivera M,Ricarte-Filho J,Knauf J,et al.Molecular genotyping of papillary thyroid carcinoma follicular variant according to its histological subtypes (encapsulated vs infiltrative) reveals distinct BRAF and RAS mutation patterns[J].Mod Pathol,2010,23(9):1191-1200.
30. Kroll TG,Sarraf P,Pecciarini L,et al.PAX8-PPAR gamma1 fusion oncogene in human thyroid carcinoma[corrected[J].Science,2000,289(5483):1357-1360.
31. Gregory Powell J,Wang X,Allard BL,et al.The PAX8/PPAR gamma fusion oncoprotein transforms immortalized human thyrocytes through a mechanism probably involving wild-type PPARgamma inhibition[J].Oncogene,2004,23(20):3634-3641.
32. Castro P,Rebocho AP,Soares RJ,et al.PAX8-PPARgamma rearrangement is frequently detected in the follicular variant of papillary thyroid carcinoma[J].J Clin Endocrinol Metab,2006,91(1):213-220.
33. Adeniran AJ,Zhu Z,Gandhi M,et al.Correlation between genetic alterations and microscopic features,clinical manifestations,and prognostic characteristics of thyroid papillary carcinomas[J].Am J Surg Pathol,2006,30(2):216-222.
34. Ohori NP,Nikiforova MN,Schoedel KE,et al.Contribution of molecular testing to thyroid fine-needle aspiration cytology of "follicular lesion of undetermined significance/atypia of undetermined significance"[J].Cancer Cytopathol,2010,118(1):17-23.
35. Schlumberger MJ,Elisei R,Bastholt L,et al.Phase Ⅱ study of safety and efficacy of motesanib in patients with progressive or symptomatic,advanced or metastatic medullary thyroid cancer[J].J Clin Oncol,2009,27(23):3794-3801.
36. Kloos RT,Ringel MD,Knopp MV,et al.Phase Ⅱ trial of sorafenib in metastatic thyroid cancer[J].J Clin Oncol,2009,27(10):1675-1684.
37. Ravaud A,de LC,Courbon F,et al.Sunitinib in patients with refractory advanced thyroid cancer:the THYSU phase Ⅱ tria[J].Oncologist,2010,15(2):212-213.
38. Carr L,Goulart B,Martins R,et al.Phase Ⅱ trial of continuous dosing of sunitinib in advanced,FDG-PET avid,medullary thyroid carcinoma (MTC) and well-differentiated thyroid cancer (WDTC)[J].J Clin Oncol,2009,27(15):6056.
39. Wells JS,Gosnell J,Gagel R,et al.Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer[J].J Clin Oncol,2010,28(5):767-772.
40. Wells SA,Robinson BG,Gagel RF,et al.Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer:a randomized,double-blind phaseⅢ trial[J].J Clin Oncol,2012,30(2):134-141.
41. Flaherty K,Puzanov I,Sosman J,et al.Phase I study of PLX4032:proof of concept for V600E BRAF mutation as a therapeutictargetin human cancer[J].J Clin Oncol (Meeting Abstracts),2009,27(Suppl):9000.
42. Schwartz GK,Robertson S,Shen A,et al.A phase I study of XL281,a selective oral RAF kinase inhibitor,in patients (Pts) with advanced solid tumors[J].J Clin Onco l (Meeting Abstracts),2009,27(Suppl):3513.

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甲状腺癌分子生物学研究进展

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