Ewha Med J.  2012 Mar;35(1):3-10. 10.12771/emj.2012.35.1.3.

Review of Molecular Markers for Thyroid Cancer

Affiliations
  • 1Department of Internal Medicine, National Rehabilitation Hospital, Seoul, Korea.
  • 2Department of Laboratory Medicine, Ewha Womans University School of Medicine, Seoul, Korea. kshong@ewha.ac.kr

Abstract

The incidence of thyroid cancer has been rapidly increased in Korea. Although fine needle aspiration cytology is recommended for diagnosis of cancer, there are some limitations. Patients with indeterminate or suspicious cytology category in which malignancy cannot be ruled out usually undergone a thyroidectomy, however, only 10~25% of them finally diagnosed as cancer. According to the progress in understanding molecular mechanism, some mutations or other molecular alterations have been studied for the diagnostic and prognostic markers for thyroid cancer. The majority of papillary thyroid cancers have BRAF and RAS mutations or RET/PTC rearrangement, and approximately 80% of follicular thyroid cancers harbor a RAS mutation or PAX8/PPARgamma rearrangement. These genetic alterations are mostly studied and current clinical guidelines suggested that these molecular markers may help management for patients with indeterminate cytology. In addition, recent studies demonstrated the high sensitivity and specificity of thyroid-stimulating hormone receptor mRNA in diagnosing cancer in patients with indeterminate cytology. For the detection of recurrent or residual thyroid cancer, serum thyroglobulin is the only circulating marker in clinical practice. However, it lacks sensitivity and is unreliable specifically in the presence of antibodies to thyroglobulin. Recent studies demonstrated a significant role of measuring the mRNA of thyroglobulin, thyroid peroxidase, thyroid-stimulating hormone receptor, and sodium/iodine symporter in peripheral blood for monitoring of the recurrence of thyroid cancer.

Keyword

Thyroid neoplasms; BRAF; RAS; Recurrence

MeSH Terms

Antibodies
Biopsy, Fine-Needle
Humans
Incidence
Iodide Peroxidase
Ion Transport
Korea
Recurrence
RNA, Messenger
Sensitivity and Specificity
Thyroglobulin
Thyroid Gland
Thyroid Neoplasms
Thyroidectomy
Thyrotropin
Antibodies
Iodide Peroxidase
RNA, Messenger
Thyroglobulin
Thyrotropin

Reference

1. Jung KW, Park S, Kong HJ, Won YJ, Lee JY, Park EC, et al. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2008. Cancer Res Treat. 2011. 43:1–11.
2. Ahn HY, Park YJ. Incidence and clinical characteristics of thyroid cancer in Korea. Korean J Med. 2009. 77:537–542.
3. Hegedus L. Clinical practice. The thyroid nodule. N Engl J Med. 2004. 351:1764–1771.
4. American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer. Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2009. 19:1167–1214.
5. Yi KH, Park YJ, Koong SS, Kim JH, Na DG, Ryu JS, et al. Revised Korean Thyroid Association management guidelines for patients with thyroid nodules and thyroid cancer. J Korean Soc Radiol. 2011. 64:389–416.
6. Adeniran AJ, Zhu Z, Gandhi M, Steward DL, Fidler JP, Giordano TJ, et al. Correlation between genetic alterations and microscopic features, clinical manifestations, and prognostic characteristics of thyroid papillary carcinomas. Am J Surg Pathol. 2006. 30:216–222.
7. Soares P, Trovisco V, Rocha AS, Lima J, Castro P, Preto A, et al. BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC. Oncogene. 2003. 22:4578–4580.
8. Wan PT, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM, et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell. 2004. 116:855–867.
9. Xing M. BRAF mutation in thyroid cancer. Endocr Relat Cancer. 2005. 12:245–262.
10. Nikiforova MN, Kimura ET, Gandhi M, Biddinger PW, Knauf JA, Basolo F, et al. BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas. J Clin Endocrinol Metab. 2003. 88:5399–5404.
11. Grieco M, Santoro M, Berlingieri MT, Melillo RM, Donghi R, Bongarzone I, et al. PTC is a novel rearranged form of the ret proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas. Cell. 1990. 60:557–563.
12. Fusco A, Santoro M, Grieco M, Carlomagno F, Dathan N, Fabien N, et al. RET/PTC activation in human thyroid carcinomas. J Endocrinol Invest. 1995. 18:127–129.
13. Nakazawa T, Kondo T, Kobayashi Y, Takamura N, Murata S, Kameyama K, et al. RET gene rearrangements (RET/PTC1 and RET/PTC3) in papillary thyroid carcinomas from an iodine-rich country (Japan). Cancer. 2005. 104:943–951.
14. Bongarzone I, Fugazzola L, Vigneri P, Mariani L, Mondellini P, Pacini F, et al. Age-related activation of the tyrosine kinase receptor protooncogenes RET and NTRK1 in papillary thyroid carcinoma. J Clin Endocrinol Metab. 1996. 81:2006–2009.
15. Fenton CL, Lukes Y, Nicholson D, Dinauer CA, Francis GL, Tuttle RM. The ret/PTC mutations are common in sporadic papillary thyroid carcinoma of children and young adults. J Clin Endocrinol Metab. 2000. 85:1170–1175.
16. Basolo F, Giannini R, Monaco C, Melillo RM, Carlomagno F, Pancrazi M, et al. Potent mitogenicity of the RET/PTC3 oncogene correlates with its prevalence in tall-cell variant of papillary thyroid carcinoma. Am J Pathol. 2002. 160:247–254.
17. Nikiforov YE. RET/PTC rearrangement in thyroid tumors. Endocr Pathol. 2002. 13:3–16.
18. Tallini G, Ghossein RA, Emanuel J, Gill J, Kinder B, Dimich AB, et al. Detection of thyroglobulin, thyroid peroxidase, and RET/PTC1 mRNA transcripts in the peripheral blood of patients with thyroid disease. J Clin Oncol. 1998. 16:1158–1166.
19. Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer. 2003. 3:11–22.
20. Esapa CT, Johnson SJ, Kendall-Taylor P, Lennard TW, Harris PE. Prevalence of Ras mutations in thyroid neoplasia. Clin Endocrinol (Oxf). 1999. 50:529–535.
21. Vasko V, Ferrand M, Di Cristofaro J, Carayon P, Henry JF, de Micco C. Specific pattern of RAS oncogene mutations in follicular thyroid tumors. J Clin Endocrinol Metab. 2003. 88:2745–2752.
22. Suarez HG, du Villard JA, Severino M, Caillou B, Schlumberger M, Tubiana M, et al. Presence of mutations in all three ras genes in human thyroid tumors. Oncogene. 1990. 5:565–570.
23. Zhu Z, Gandhi M, Nikiforova MN, Fischer AH, Nikiforov YE. Molecular profile and clinical-pathologic features of the follicular variant of papillary thyroid carcinoma. An unusually high prevalence of ras mutations. Am J Clin Pathol. 2003. 120:71–77.
24. Kroll TG, Sarraf P, Pecciarini L, Chen CJ, Mueller E, Spiegelman BM, et al. PAX8-PPARgamma1 fusion oncogene in human thyroid carcinoma. Science. 2000. 289:1357–1360.
25. Au AY, McBride C, Wilhelm KG Jr, Koenig RJ, Speller B, Cheung L, et al. PAX8-peroxisome proliferator-activated receptor gamma (PPARgamma) disrupts normal PAX8 or PPARgamma transcriptional function and stimulates follicular thyroid cell growth. Endocrinology. 2006. 147:367–376.
26. Castro P, Rebocho AP, Soares RJ, Magalhaes J, Roque L, Trovisco V, et al. PAX8-PPARgamma rearrangement is frequently detected in the follicular variant of papillary thyroid carcinoma. J Clin Endocrinol Metab. 2006. 91:213–220.
27. Cheung L, Messina M, Gill A, Clarkson A, Learoyd D, Delbridge L, et al. Detection of the PAX8-PPAR gamma fusion oncogene in both follicular thyroid carcinomas and adenomas. J Clin Endocrinol Metab. 2003. 88:354–357.
28. Dwight T, Thoppe SR, Foukakis T, Lui WO, Wallin G, Hoog A, et al. Involvement of the PAX8/peroxisome proliferator-activated receptor gamma rearrangement in follicular thyroid tumors. J Clin Endocrinol Metab. 2003. 88:4440–4445.
29. Freitas BC, Cerutti JM. Genetic markers differentiating follicular thyroid carcinoma from benign lesions. Mol Cell Endocrinol. 2010. 321:77–85.
30. French CA, Alexander EK, Cibas ES, Nose V, Laguette J, Faquin W, et al. Genetic and biological subgroups of low-stage follicular thyroid cancer. Am J Pathol. 2003. 162:1053–1060.
31. He H, Jazdzewski K, Li W, Liyanarachchi S, Nagy R, Volinia S, et al. The role of microRNA genes in papillary thyroid carcinoma. Proc Natl Acad Sci U S A. 2005. 102:19075–19080.
32. Pallante P, Visone R, Ferracin M, Ferraro A, Berlingieri MT, Troncone G, et al. MicroRNA deregulation in human thyroid papillary carcinomas. Endocr Relat Cancer. 2006. 13:497–508.
33. Tetzlaff MT, Liu A, Xu X, Master SR, Baldwin DA, Tobias JW, et al. Differential expression of miRNAs in papillary thyroid carcinoma compared to multinodular goiter using formalin fixed paraffin embedded tissues. Endocr Pathol. 2007. 18:163–173.
34. Visone R, Russo L, Pallante P, De Martino I, Ferraro A, Leone V, et al. MicroRNAs (miR)-221 and miR-222, both overexpressed in human thyroid papillary carcinomas, regulate p27Kip1 protein levels and cell cycle. Endocr Relat Cancer. 2007. 14:791–798.
35. Nikiforova MN, Tseng GC, Steward D, Diorio D, Nikiforov YE. MicroRNA expression profiling of thyroid tumors: biological significance and diagnostic utility. J Clin Endocrinol Metab. 2008. 93:1600–1608.
36. Baloch ZW, LiVolsi VA, Asa SL, Rosai J, Merino MJ, Randolph G, et al. Diagnostic terminology and morphologic criteria for cytologic diagnosis of thyroid lesions: a synopsis of the National Cancer Institute Thyroid Fine-Needle Aspiration State of the Science Conference. Diagn Cytopathol. 2008. 36:425–437.
37. Theoharis CG, Schofield KM, Hammers L, Udelsman R, Chhieng DC. The Bethesda thyroid fine-needle aspiration classification system: year 1 at an academic institution. Thyroid. 2009. 19:1215–1223.
38. Baloch ZW, Fleisher S, LiVolsi VA, Gupta PK. Diagnosis of "follicular neoplasm": a gray zone in thyroid fine-needle aspiration cytology. Diagn Cytopathol. 2002. 26:41–44.
39. Faquin WC, Baloch ZW. Fine-needle aspiration of follicular patterned lesions of the thyroid: Diagnosis, management, and follow-up according to National Cancer Institute (NCI) recommendations. Diagn Cytopathol. 2010. 38:731–739.
40. Yang J, Schnadig V, Logrono R, Wasserman PG. Fine-needle aspiration of thyroid nodules: a study of 4703 patients with histologic and clinical correlations. Cancer. 2007. 111:306–315.
41. Layfield LJ, Morton MJ, Cramer HM, Hirschowitz S. Implications of the proposed thyroid fine-needle aspiration category of "follicular lesion of undetermined significance": a five-year multi-institutional analysis. Diagn Cytopathol. 2009. 37:710–714.
42. Nayar R, Ivanovic M. The indeterminate thyroid fine-needle aspiration: experience from an academic center using terminology similar to that proposed in the 2007 National Cancer Institute Thyroid Fine Needle Aspiration State of the Science Conference. Cancer. 2009. 117:195–202.
43. Shi Y, Ding X, Klein M, Sugrue C, Matano S, Edelman M, et al. Thyroid fine-needle aspiration with atypia of undetermined significance: a necessary or optional category? Cancer. 2009. 117:298–304.
44. Gharib H, Goellner JR, Johnson DA. Fine-needle aspiration cytology of the thyroid: a 12-year experience with 11,000 biopsies. Clin Lab Med. 1993. 13:699–709.
45. Ravetto C, Colombo L, Dottorini ME. Usefulness of fine-needle aspiration in the diagnosis of thyroid carcinoma: a retrospective study in 37,895 patients. Cancer. 2000. 90:357–363.
46. Castro MR, Gharib H. Thyroid fine-needle aspiration biopsy: progress, practice, and pitfalls. Endocr Pract. 2003. 9:128–136.
47. Castro MR, Gharib H. Continuing controversies in the management of thyroid nodules. Ann Intern Med. 2005. 142:926–931.
48. Kumagai A, Namba H, Akanov Z, Saenko VA, Meirmanov S, Ohtsuru A, et al. Clinical implications of pre-operative rapid BRAF analysis for papillary thyroid cancer. Endocr J. 2007. 54:399–405.
49. Sapio MR, Posca D, Raggioli A, Guerra A, Marotta V, Deandrea M, et al. Detection of RET/PTC, TRK and BRAF mutations in preoperative diagnosis of thyroid nodules with indeterminate cytological findings. Clin Endocrinol (Oxf). 2007. 66:678–683.
50. Jo YS, Huang S, Kim YJ, Lee IS, Kim SS, Kim JR, et al. Diagnostic value of pyrosequencing for the BRAF V600E mutation in ultrasound-guided fine-needle aspiration biopsy samples of thyroid incidentalomas. Clin Endocrinol (Oxf). 2009. 70:139–144.
51. Pizzolanti G, Russo L, Richiusa P, Bronte V, Nuara RB, Rodolico V, et al. Fine-needle aspiration molecular analysis for the diagnosis of papillary thyroid carcinoma through BRAF V600E mutation and RET/PTC rearrangement. Thyroid. 2007. 17:1109–1115.
52. Cantara S, Capezzone M, Marchisotta S, Capuano S, Busonero G, Toti P, et al. Impact of proto-oncogene mutation detection in cytological specimens from thyroid nodules improves the diagnostic accuracy of cytology. J Clin Endocrinol Metab. 2010. 95:1365–1369.
53. Nikiforov YE, Steward DL, Robinson-Smith TM, Haugen BR, Klopper JP, Zhu Z, et al. Molecular testing for mutations in improving the fine-needle aspiration diagnosis of thyroid nodules. J Clin Endocrinol Metab. 2009. 94:2092–2098.
54. Vdovichenko KK, Markova SI, Belokhvostov AS. Mutant form of BRAF gene in blood plasma of cancer patients. Ann N Y Acad Sci. 2004. 1022:228–231.
55. Wagner K, Arciaga R, Siperstein A, Milas M, Warshawsky I, Sethu S, et al. Thyrotropin receptor/thyroglobulin messenger ribonucleic acid in peripheral blood and fine-needle aspiration cytology: diagnostic synergy for detecting thyroid cancer. J Clin Endocrinol Metab. 2005. 90:1921–1924.
56. Chia SY, Milas M, Reddy SK, Siperstein A, Skugor M, Brainard J, et al. Thyroid-stimulating hormone receptor messenger ribonucleic acid measurement in blood as a marker for circulating thyroid cancer cells and its role in the preoperative diagnosis of thyroid cancer. J Clin Endocrinol Metab. 2007. 92:468–475.
57. Fugazzola L, Mihalich A, Persani L, Cerutti N, Reina M, Bonomi M, et al. Highly sensitive serum thyroglobulin and circulating thyroglobulin mRNA evaluations in the management of patients with differentiated thyroid cancer in apparent remission. J Clin Endocrinol Metab. 2002. 87:3201–3208.
58. Grammatopoulos D, Elliott Y, Smith SC, Brown I, Grieve RJ, Hillhouse EW, et al. Measurement of thyroglobulin mRNA in peripheral blood as an adjunctive test for monitoring thyroid cancer. Mol Pathol. 2003. 56:162–166.
59. Bojunga J, Roddiger S, Stanisch M, Kusterer K, Kurek R, Renneberg H, et al. Molecular detection of thyroglobulin mRNA transcripts in peripheral blood of patients with thyroid disease by RT-PCR. Br J Cancer. 2000. 82:1650–1655.
60. Cradic KW, Milosevic D, Rosenberg AM, Erickson LA, McIver B, Grebe SK. Mutant BRAF(T1799A) can be detected in the blood of papillary thyroid carcinoma patients and correlates with disease status. J Clin Endocrinol Metab. 2009. 94:5001–5009.
61. Chuang TC, Chuang AY, Poeta L, Koch WM, Califano JA, Tufano RP. Detectable BRAF mutation in serum DNA samples from patients with papillary thyroid carcinomas. Head Neck. 2010. 32:229–234.
62. Gianoukakis AG, Giannelli SM, Salameh WA, McPhaul LW. Well differentiated follicular thyroid neoplasia: impact of molecular and technological advances on detection, monitoring and treatment. Mol Cell Endocrinol. 2011. 332:9–20.
63. Bellantone R, Lombardi CP, Bossola M, Ferrante A, Princi P, Boscherini M, et al. Validity of thyroglobulin mRNA assay in peripheral blood of postoperative thyroid carcinoma patients in predicting tumor recurrences varies according to the histologic type: results of a prospective study. Cancer. 2001. 92:2273–2279.
64. Bugalho MJ, Domingues RS, Pinto AC, Garrao A, Catarino AL, Ferreira T, et al. Detection of thyroglobulin mRNA transcripts in peripheral blood of individuals with and without thyroid glands: evidence for thyroglobulin expression by blood cells. Eur J Endocrinol. 2001. 145:409–413.
65. Elisei R, Vivaldi A, Agate L, Molinaro E, Nencetti C, Grasso L, et al. Low specificity of blood thyroglobulin messenger ribonucleic acid assay prevents its use in the follow-up of differentiated thyroid cancer patients. J Clin Endocrinol Metab. 2004. 89:33–39.
66. Karavitaki N, Lembessis P, Tzanela M, Vlassopoulou V, Thalassinos N, Koutsilieris M. Molecular staging using qualitative RT-PCR analysis detecting thyreoglobulin mRNA in the peripheral blood of patients with differentiated thyroid cancer after therapy. Anticancer Res. 2005. 25:3135–3142.
67. Ringel MD, Ladenson PW, Levine MA. Molecular diagnosis of residual and recurrent thyroid cancer by amplification of thyroglobulin messenger ribonucleic acid in peripheral blood. J Clin Endocrinol Metab. 1998. 83:4435–4442.
68. Ishikawa T, Miwa M, Uchida K. Quantitation of thyroid peroxidase mRNA in peripheral blood for early detection of thyroid papillary carcinoma. Thyroid. 2006. 16:435–442.
69. Mercken L, Simons MJ, Brocas H, Vassart G. Alternative splicing may be responsible for heterogeneity of thyroglobulin structure. Biochimie. 1989. 71:223–226.
70. Chinnappa P, Taguba L, Arciaga R, Faiman C, Siperstein A, Mehta AE, et al. Detection of thyrotropin-receptor messenger ribonucleic acid (mRNA) and thyroglobulin mRNA transcripts in peripheral blood of patients with thyroid disease: sensitive and specific markers for thyroid cancer. J Clin Endocrinol Metab. 2004. 89:3705–3709.
71. Barzon L, Boscaro M, Pacenti M, Taccaliti A, Palu G. Evaluation of circulating thyroid-specific transcripts as markers of thyroid cancer relapse. Int J Cancer. 2004. 110:914–920.
Full Text Links
  • EMJ
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr