Abstract
Purpose
The role of thyroid-specific transcription factors in thyroid malignancy is still poorly understood, so we investigate thyroid-specific transcription factors gene expression both in benign and in malignant thyroid nodules, aiming to study a possible clinical utility of these molecules.
Methods
We quantified TTF-1, FOXE1 and PAX8 mRNA levels, relating their expression to diagnostic and prognostic features of thyroid tumors. RNA was extracted from 4 normal thyroid tissues, 101 malignant [99 papillary thyroid carcinomas (PTC) and 2 anaplastic thyroid carcinomas] and 99 benign thyroid lesion tissues [49 goiter and 50 follicular adenomas (FA)].
Results
Levels of mRNA of both FOXE1 (P < 0.0001) and PAX8 (P < 0.0001) genes, but not TTF-1 (P = 0.7056), were higher in benign than in malignant thyroid lesions. FOXE1 was able to identify malignant nodules with 75.8 % sensitivity, 76.1 % specificity, 75.8 % positive predictive value, 76.1 % negative predictive value and 75.9 % accuracy. PAX8 was able to identify malignancy with 60.6 % sensitivity, 81.1 % specificity, 76.9 % positive predictive value, 66.4 % negative predictive value and 70.6 % accuracy. Both FOXE1 and PAX8 gene expression patterns were also able to differentiate FA from the follicular variant of PTC-FVPTC. However, the investigated gene expression was neither associated with any clinical feature of tumor aggressiveness nor associated with recurrence or survival.
Conclusions
We suggest that FOXE1 and PAX8 gene expression patterns may help to diagnose thyroid nodules, identifying malignancy and characterizing follicular-patterned thyroid lesions, but are not determinants of thyroid tumor progression.
Similar content being viewed by others
References
Nikiforov YE, Nikiforova MN (2011) Molecular genetics and diagnosis of thyroid cancer. Nat Rev Endocrinol 7(10):569–580. doi:10.1038/nrendo.2011.142
American Thyroid Association Guidelines Taskforce on Thyroid N, Differentiated Thyroid C, Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, Mazzaferri EL, McIver B, Pacini F, Schlumberger M, Sherman SI, Steward DL, Tuttle RM (2009) Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 19(11):1167–1214. doi:10.1089/thy.2009.0110
Pitoia F, Ward L, Wohllk N, Friguglietti C, Tomimori E, Gauna A, Camargo R, Vaisman M, Harach R, Munizaga F, Corigliano S, Pretell E, Niepomniszcze H (2009) Recommendations of the Latin American Thyroid Society on diagnosis and management of differentiated thyroid cancer. Arquivos brasileiros de endocrinologia e metabologia 53(7):884–887
Ahn HS, Kim HJ, Welch HG (2014) Korea’s thyroid-cancer “epidemic”–screening and overdiagnosis. N Engl J Med 371(19):1765–1767. doi:10.1056/NEJMp1409841
Melillo RM, Santoro M (2012) Molecular biomarkers in thyroid FNA samples. J Clin Endocrinol Metab 97(12):4370–4373. doi:10.1210/jc.2012-3730
Wang CC, Friedman L, Kennedy GC, Wang H, Kebebew E, Steward DL, Zeiger MA, Westra WH, Wang Y, Khanafshar E, Fellegara G, Rosai J, Livolsi V, Lanman RB (2011) A large multicenter correlation study of thyroid nodule cytopathology and histopathology. Thyroid 21(3):243–251. doi:10.1089/thy.2010.0243
Bryson PC, Shores CG, Hart C, Thorne L, Patel MR, Richey L, Farag A, Zanation AM (2008) Immunohistochemical distinction of follicular thyroid adenomas and follicular carcinomas. Arch Otolaryngol Head Neck Surg 134(6):581–586. doi:10.1001/archotol.134.6.581
Ward LS, Kloos RT (2013) Molecular markers in the diagnosis of thyroid nodules. Arquivos brasileiros de endocrinologia e metabologia 57(2):89–97
Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60(5):277–300. doi:10.3322/caac.20073
Ponzoni M, Arrigoni G, Doglioni C (2007) New transcription factors in diagnostic hematopathology. Adv Anat Pathol 14(1):25–35. doi:10.1097/PAP.0b013e31802f0495
Guazzi S, Price M, De Felice M, Damante G, Mattei MG, Di Lauro R (1990) Thyroid nuclear factor 1 (TTF-1) contains a homeodomain and displays a novel DNA binding specificity. EMBO J 9(11):3631–3639
Lonigro R, De Felice M, Biffali E, Macchia PE, Damante G, Asteria C, Di Lauro R (1996) Expression of thyroid transcription factor 1 gene can be regulated at the transcriptional and posttranscriptional levels. Cell Growth Differ 7(2):251–261
Civitareale D, Saiardi A, Falasca P (1994) Purification and characterization of thyroid transcription factor 2. Biochem J 304(Pt 3):981–985
Zannini M, Avantaggiato V, Biffali E, Arnone MI, Sato K, Pischetola M, Taylor BA, Phillips SJ, Simeone A, Di Lauro R (1997) TTF-2, a new forkhead protein, shows a temporal expression in the developing thyroid which is consistent with a role in controlling the onset of differentiation. EMBO J 16(11):3185–3197. doi:10.1093/emboj/16.11.3185
Plachov D, Chowdhury K, Walther C, Simon D, Guenet JL, Gruss P (1990) Pax8, a murine paired box gene expressed in the developing excretory system and thyroid gland. Development 110(2):643–651
Gudmundsson J, Sulem P, Gudbjartsson DF, Jonasson JG, Sigurdsson A, Bergthorsson JT, He H, Blondal T, Geller F, Jakobsdottir M, Magnusdottir DN, Matthiasdottir S, Stacey SN, Skarphedinsson OB, Helgadottir H, Li W, Nagy R, Aguillo E, Faure E, Prats E, Saez B, Martinez M, Eyjolfsson GI, Bjornsdottir US, Holm H, Kristjansson K, Frigge ML, Kristvinsson H, Gulcher JR, Jonsson T, Rafnar T, Hjartarsson H, Mayordomo JI, de la Chapelle A, Hrafnkelsson J, Thorsteinsdottir U, Kong A, Stefansson K (2009) Common variants on 9q22.33 and 14q13.3 predispose to thyroid cancer in European populations. Nat Genet 41(4):460–464. doi:10.1038/ng.339
Ngan ES, Lang BH, Liu T, Shum CK, So MT, Lau DK, Leon TY, Cherny SS, Tsai SY, Lo CY, Khoo US, Tam PK, Garcia-Barcelo MM (2009) A germline mutation (A339 V) in thyroid transcription factor-1 (TITF-1/NKX2.1) in patients with multinodular goiter and papillary thyroid carcinoma. J Natl Cancer Inst 101(3):162–175. doi:10.1093/jnci/djn471
Kroll TG, Sarraf P, Pecciarini L, Chen CJ, Mueller E, Spiegelman BM, Fletcher JA (2000) PAX8-PPARgamma1 fusion oncogene in human thyroid carcinoma [corrected]. Science 289(5483):1357–1360
Kallel R, Belguith-Maalej S, Akdi A, Mnif M, Charfeddine I, Galofre P, Ghorbel A, Abid M, Marcos R, Ayadi H, Velazquez A, Hadj Kacem H (2010) Genetic investigation of FOXE1 polyalanine tract in thyroid diseases: new insight on the role of FOXE1 in thyroid carcinoma. Cancer Biomark 8(1):43–51. doi:10.3233/DMA-2011-0824
Kimura S (2011) Thyroid-specific transcription factors and their roles in thyroid cancer. J Thyroid Res 2011:710213. doi:10.4061/2011/710213
Nonaka D, Tang Y, Chiriboga L, Rivera M, Ghossein R (2008) Diagnostic utility of thyroid transcription factors Pax8 and TTF-2 (FoxE1) in thyroid epithelial neoplasms. Mod Pathol 21(2):192–200. doi:10.1038/modpathol.3801002
Zhang P, Zuo H, Nakamura Y, Nakamura M, Wakasa T, Kakudo K (2006) Immunohistochemical analysis of thyroid-specific transcription factors in thyroid tumors. Pathol Int 56(5):240–245. doi:10.1111/j.1440-1827.2006.01959.x
Fabbro D, Di Loreto C, Beltrami CA, Belfiore A, Di Lauro R, Damante G (1994) Expression of thyroid-specific transcription factors TTF-1 and PAX-8 in human thyroid neoplasms. Cancer Res 54(17):4744–4749
Sequeira MJ, Morgan JM, Fuhrer D, Wheeler MH, Jasani B, Ludgate M (2001) Thyroid transcription factor-2 gene expression in benign and malignant thyroid lesions. Thyroid 11(11):995–1001. doi:10.1089/105072501753271662
Fan Y, Ding Z, Yang Z, Deng X, Kang J, Wu B, Zheng Q (2013) Expression and clinical significance of FOXE1 in papillary thyroid carcinoma. Mol Med Rep 8(1):123–127. doi:10.3892/mmr.2013.1494
Lacroix L, Mian C, Barrier T, Talbot M, Caillou B, Schlumberger M, Bidart JM (2004) PAX8 and peroxisome proliferator-activated receptor gamma 1 gene expression status in benign and malignant thyroid tissues. Euro J Endocrinol 151(3):367–374
Lacroix L, Michiels S, Mian C, Arturi F, Caillou B, Filetti S, Schlumberger M, Bidart JM (2006) HEX, PAX-8 and TTF-1 gene expression in human thyroid tissues: a comparative analysis with other genes involved in iodide metabolism. Clin Endocrinol 64(4):398–404. doi:10.1111/j.1365-2265.2006.02477.x
Katoh R, Kawaoi A, Miyagi E, Li X, Suzuki K, Nakamura Y, Kakudo K (2000) Thyroid transcription factor-1 in normal, hyperplastic, and neoplastic follicular thyroid cells examined by immunohistochemistry and nonradioactive in situ hybridization. Mod Pathol 13(5):570–576. doi:10.1038/modpathol.3880098
Kondo T, Nakazawa T, Ma D, Niu D, Mochizuki K, Kawasaki T, Nakamura N, Yamane T, Kobayashi M, Katoh R (2009) Epigenetic silencing of TTF-1/NKX2-1 through DNA hypermethylation and histone H3 modulation in thyroid carcinomas. Lab Investig J Tech Methods Pathol 89(7):791–799. doi:10.1038/labinvest.2009.50
van Staveren WC, Solis DW, Delys L, Duprez L, Andry G, Franc B, Thomas G, Libert F, Dumont JE, Detours V, Maenhaut C (2007) Human thyroid tumor cell lines derived from different tumor types present a common dedifferentiated phenotype. Cancer Res 67(17):8113–8120. doi:10.1158/0008-5472.CAN-06-4026
Acknowledgments
The authors thank Etna Macário for the language services provided. A special thank to our group from the Laboratory of Cancer Molecular Genetics (GEMOCA) of the School of Medical Sciences.
Funding
This study received financial support from the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Grant # 2013/18683-7.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent
Consent has been obtained from each patient after full explanation of the purpose and nature of all procedures.
Rights and permissions
About this article
Cite this article
Batista, F.A., Ward, L.S., Marcello, M.A. et al. Gene expression of thyroid-specific transcription factors may help diagnose thyroid lesions but are not determinants of tumor progression. J Endocrinol Invest 39, 423–429 (2016). https://doi.org/10.1007/s40618-015-0386-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40618-015-0386-4