TERT promoter mutations and their correlation with BRAF and RAS mutations in a consecutive cohort of 145 thyroid cancer cases

Cacciato Insilla,Andrea; Proietti,Agnese; Borrelli,Nicla; Macerola,Elisabetta; Niccoli,Cristina; Vitti,Paolo; Miccoli,Paolo; Basolo,Fulvio

doi:10.3892/ol.2017.7675

TERT promoter mutations and their correlation with BRAF and RAS mutations in a consecutive cohort of 145 thyroid cancer cases

Authors:
- Andrea Cacciato Insilla
- Agnese Proietti
- Nicla Borrelli
- Elisabetta Macerola
- Cristina Niccoli
- Paolo Vitti
- Paolo Miccoli
- Fulvio Basolo
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Affiliations: Department of Surgical Pathology, University Hospital of Pisa, I‑56126 Pisa, Italy, Department of Endocrinology, University Hospital of Pisa, I‑56126 Pisa, Italy, Department of Endocrine Surgery, University Hospital of Pisa, I‑56126 Pisa, Italy
Published online on: December 21, 2017 https://doi.org/10.3892/ol.2017.7675
Pages: 2763-2770
Copyright: © Cacciato Insilla et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Papillary thyroid carcinoma (PTC) is the most common type of endocrine malignancy and accounts for ~80% of thyroid carcinomas in adults and 90% in children. Risk stratification is important for identifying patients at higher risk and, for this reason, recent advances in molecular genetics of thyroid cancer can be applied to provide novel biomarkers useful in understanding tumor behavior. B‑Raf proto‑oncogene, serine/threonine kinase (BRAF) and rat sarcoma (RAS) mutations have been widely studied and appear to have an important role in thyroid tumorigenesis. Somatic telomerase reverse transcriptase (TERT) promoter mutations have been recently identified in several types of malignant tumors, including thyroid neoplasia; however, the actual role of TERT mutations in thyroid tumorigenesis is still under debate. In the present study, the mutational status of BRAF, RAS and TERT was analyzed in order to elucidate the roles of these genes in thyroid tumorigenesis. The TERT mutational analysis was also correlated with an immunohistochemical study of TERT protein expression. According to the literature, our data provide evidence of the BRAF and RAS roles in thyroid tumorigenesis, supporting an association between BRAF (V600E) mutations and the more aggressive clinical and pathological features of thyroid tumors. By contrast, TERT mutations were not significantly associated with any clinical parameters; therefore, its role in initial tumorigenesis should be further investigated.

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1	Erickson Lori A: Papillary thyroid carcinoma. Atlas of Endocrine Pathology. 1–50. 2014. View Article : Google Scholar
2	Rahbari R, Zhang L and Kebebew E: Thyroid cancer gender disparity. Future Oncol. 6:1771–1779. 2010. View Article : Google Scholar : PubMed/NCBI
3	Sipos JA and Mazzaferri EL: Thyroid cancer epidemiology and prognostic variables. Clin Oncol (R Coll Radiol). 22:395–404. 2010. View Article : Google Scholar : PubMed/NCBI
4	Caron NR and Clark OH: Papillary thyroid cancer. Curr Treat Options Oncol. 7:309–319. 2006. View Article : Google Scholar : PubMed/NCBI
5	Xing M, Westra WH, Tufano RP, Cohen Y, Rosenbaum E, Rhoden KJ, Carson KA, Vasko V, Larin A, Tallini G, et al: BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. J Clin Endocrinol Metab. 90:6373–6379. 2005. View Article : Google Scholar : PubMed/NCBI
6	Nikiforov YE: Molecular diagnostics of thyroid tumors. Arch Pathol Lab Med. 135:569–577. 2011.PubMed/NCBI
7	Pelizzo MR, Dobrinja C, Casal Ide E, Zane M, Lora O, Toniato A, Mian C, Barollo S, Izuzquiza M, Guerrini J, et al: The role of BRAF(V600E) mutation as poor prognostic factor for the outcome of patients with intrathyroid papillary thyroid carcinoma. Biomed Pharmacother. 68:413–417. 2014. View Article : Google Scholar : PubMed/NCBI
8	Afkhami M, Karunamurthy A, Chiosea S, Nikiforova MN, Seethala R, Nikiforov YE and Coyne C: Histopathologic and clinical characterization of thyroid tumors carrying the BRAF K601E mutation. Thyroid. 26:242–247. 2016. View Article : Google Scholar : PubMed/NCBI
9	Jara SM, Bhatnagar R, Guan H, Gocke CD, Ali SZ and Tufano RP: Utility of BRAF mutation detection in fine-needle aspiration biopsy samples read as ‘suspicious for papillary thyroid carcinoma’. Head Neck. 37:1788–1793. 2015. View Article : Google Scholar : PubMed/NCBI
10	Macerola E, Loggini B, Giannini R, Garavello G, Giordano M, Proietti A, Niccoli C, Basolo F and Fontanini G: Coexistence of TERT promoter and BRAF mutations in cutaneous melanoma is associated with more clinicopathological features of aggressiveness. Virchows Arch. 467:177–184. 2015. View Article : Google Scholar : PubMed/NCBI
11	Xing M: Clinical utility of RAS mutations in thyroid cancer: A blurred picture now emerging clearer. BMC Med. 14:122016. View Article : Google Scholar : PubMed/NCBI
12	Vinagre J, Almeida A, Pópulo H, Batista R, Lyra J, Pinto V, Coelho R, Celestino R, Prazeres H, Lima L, et al: Frequency of TERT promoter mutations in human cancers. Nat Commun. 4:21852013. View Article : Google Scholar : PubMed/NCBI
13	Muzza M, Colombo C, Rossi S, Tosi D, Cirello V, Perrino M, De Leo S, Magnani E, Pignatti E, Vigo B, et al: Telomerase in differentiated thyroid cancer: Promoter mutations, expression and localization. Mol Cell Endocrinol. 399:288–295. 2015. View Article : Google Scholar : PubMed/NCBI
14	Park CK, Lee SH, Kim JY, Kim JE, Kim TM, Lee ST, Choi SH, Park SH and Kim IH: Expression level of hTERT is regulated by somatic mutation and common single nucleotide polymorphism at promoter region in glioblastoma. Oncotarget. 5:3399–3407. 2014. View Article : Google Scholar : PubMed/NCBI
15	Liu X, Bishop J, Shan Y, Pai S, Liu D, Murugan AK, Sun H, El-Naggar AK and Xing M: Highly prevalent TERT promoter mutations in aggressive thyroid cancers. Endocr Relat Cancer. 20:603–610. 2013. View Article : Google Scholar : PubMed/NCBI
16	Horn S, Figl A, Rachakonda PS, Fischer C, Sucker A, Gast A, Kadel S, Moll I, Nagore E, Hemminki K, et al: TERT promoter mutations in familial and sporadic melanoma. Science. 339:959–961. 2013. View Article : Google Scholar : PubMed/NCBI
17	Yarchoan M, LiVolsi VA and Brose MS: BRAF mutation and thyroid cancer recurrence. J Clin Oncol. 33:7–8. 2015. View Article : Google Scholar : PubMed/NCBI
18	Gandolfi G, Ragazzi M, Frasoldati A, Piana S, Ciarocchi A and Sancisi V: TERT promoter mutations are associated with distant metastases in papillary thyroid carcinoma. Eur J Endocrinol. 172:403–413. 2015. View Article : Google Scholar : PubMed/NCBI
19	Esserman LJ, Thompson IM Jr and Reid B: Overdiagnosis and overtreatment in cancer: An opportunity for improvement. JAMA. 310:797–798. 2013. View Article : Google Scholar : PubMed/NCBI
20	Torregrossa L, Viola D, Sensi E, Giordano M, Piaggi P, Romei C, Materazzi G, Miccoli P, Elisei R and Basolo F: Papillary thyroid carcinoma with rare exon 15 BRAF mutation has indolent behavior: A single-institution experience. J Clin Endocrinol Metab. 101:4413–4420. 2016. View Article : Google Scholar : PubMed/NCBI
21	Shi X, Liu R, Qu S, Zhu G, Bishop J, Liu X, Sun H, Shan Z, Wang E, Luo Y, et al: Association of TERT promoter mutation 1,295,228 C>T with BRAF V600E mutation, older patient age and distant metastasis in anaplastic thyroid cancer. J Clin Endocrinol Metab. 100:E632–E637. 2015. View Article : Google Scholar : PubMed/NCBI
22	Xing M, Liu R, Liu X, Murugan AK, Zhu G, Zeiger MA, Pai S and Bishop J: BRAF V600E and TERT promoter mutations cooperatively identify the most aggressive papillary thyroid cancer with highest recurrence. J Clin Oncol. 32:2718–2726. 2014. View Article : Google Scholar : PubMed/NCBI