Abstract
Purpose
Locally advanced papillary thyroid cancer (LAPTC) has poor prognosis. Large-scale genomic testing has revealed multiple oncogenic drivers which may be essential for understanding tumor progression. However, the accurate identification of high recurrence risk and poor prognosis in thyroid carcinoma remains unclear. The objective of this study was to analyze genetic profile and clinicopathologic features of locally advanced papillary thyroid cancers.
Methods
An observational cohort study was performed to identify molecular characteristics of LAPTC and a prognosis comparison of LAPTC with different genetic mutations. ThyroSeq v2 next-generation sequencing (57-gene panel) was performed on fresh tumor tissue. Then, the clinicopathological features between tumors with different genetic mutations were compared. Additionally, correlations of tumor recurrence and disease free survival with different genetic alterations were analyzed.
Results
This study showed that the main mutation is common BRAFV600E (66.2%, 43/65) in LAPTC, followed by the TERT promoter mutations (38.5%, 25/65). Synergetic mutations of BRAFV600E and TERT promoters (B&T) were identified in 26.2% LAPTC (17/65), which is associated with tall-cell variant, extrathyroidal invasion and advanced tumor stage (III/IV). The synergetic mutations of B&T are also significantly associated with higher risk of recurrence (hazard ratio [HR], 6.0; 95% confidence interval, CI 1.26–28.55, P = 0.02) and mortality (17.6%, 3/17).
Conclusions
Synergetic mutations of B&T are common in LAPTC, which is associated with the aggressive clinicopathologic features and an increased risk of recurrence and mortality. This finding may help to predict aggressive behavior of LAPTC and to assist in clinical decision-making.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
Study data will be made available upon request and with appropriate institutional approvals.
References
Alzahrani AS, Alsaadi R, Murugan AK, Sadiq BB (2016) TERT promoter mutations in thyroid cancer. Horm Cancer 7:165–177
Bai Y, Kakudo K, Jung CK (2020) Updates in the pathologic classification of thyroid neoplasms: a review of the World Health Organization Classification. Endocrinol Metab (Seoul) 35:696–715
Brzezianska E, Pastuszak-Lewandoska D, Wojciechowska K, Migdalska-Sek M, Cyniak-Magierska A, Nawrot E et al (2007) Investigation of V600E BRAF mutation in papillary thyroid carcinoma in the Polish population. Neuro Endocrinol Lett 28:351–359
Colombo C, Muzza M, Proverbio MC, Tosi D, Soranna D, Pesenti C et al (2019) Impact of mutation density and heterogeneity on papillary thyroid cancer clinical features and remission probability. Thyroid 29:237–251
Durante C, Montesano T, Torlontano M, Attard M, Monzani F, Tumino S et al (2013) Papillary thyroid cancer: time course of recurrences during post-surgery surveillance. J Clin Endocrinol Metab 98:636–642
Elisei R, Ugolini C, Viola D, Lupi C, Biagini A, Giannini R et al (2008) BRAF(V600E) mutation and outcome of patients with papillary thyroid carcinoma: a 15-year median follow-up study. J Clin Endocrinol Metab 93:3943–3949
Ana P Estrada-Flórez, Mabel E Bohórquez, Alejandro Vélez, Carlos S Duque, Jorge H Donado, Gilbert Mateus et al (2019) BRAF and TERT mutations in papillary thyroid cancer patients of Latino ancestry. Endocr Connect 8(9):1310–1317
Gandolfi G, Sancisi V, Piana S, Ciarrocchi A (2015) Time to re-consider the meaning of BRAF V600E mutation in papillary thyroid carcinoma. Int J Cancer 137:1001–1011
Gouveia C, Can NT, Bostrom A, Grenert JP, van Zante A, Orloff LA (2013) Lack of association of BRAF mutation with negative prognostic indicators in papillary thyroid carcinoma: the University of California, San Francisco, experience. JAMA Otolaryngol Head Neck Surg 139:1164–1170
Griewank KG, Murali R, Puig-Butille JA, Schilling B, Livingstone E, Potrony M et al (2014) TERT promoter mutation status as an independent prognostic factor in cutaneous melanoma. J Natl Cancer Institut 106:dju246
Huang FW, Hodis E, Xu MJ, Kryukov GV, Chin L, Garraway LA (2013) Highly recurrent TERT promoter mutations in human melanoma. Science 339:957–959
Killela PJ, Reitman ZJ, Jiao YC, Bettegowda C, Agrawal N, Diaz LA Jr et al (2013) TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc Natl Acad Sci USA 110:6021–6026
La Vecchia C, Malvezzi M, Bosetti C, Garavello W, Bertuccio P, Levi F et al (2015) Thyroid cancer mortality and incidence: a global overview. Int J Cancer 136:2187–2195
Landa I, Ganly I, Chan TA, Mitsutake N, Matsuse M, Ibrahimpasic T et al (2013) Frequent somatic TERT promoter mutations in thyroid cancer: higher prevalence in advanced forms of the disease. J Clin Endocrinol Metab 98:E1562–E1566
Li C, Lee KC, Schneider EB, Zeiger MA (2012) BRAF V600E mutation and its association with clinicopathological features of papillary thyroid cancer: a meta-analysis. J Clin Endocrinol Metab 97:4559–4570
Liu R, Xing M (2016) TERT promoter mutations in thyroid cancer. Endocr Relat Cancer 23:143–155
Liu X, Bishop J, Shan Y, Pai S, Liu D, Murugan AK et al (2013) Highly prevalent TERT promoter mutations in aggressive thyroid cancers. Endocr Relat Cancer 20:603–610
Liu X, Qu S, Liu R, Sheng C, Shi X, Zhu G et al (2014) TERT promoter mutations and their association with BRAF V600E mutation and aggressive clinicopathological characteristics of thyroid cancer. J Clin Endocrinol Metab 99:E1130-1136
Lloyd R, Osamura R, Klöppel G, Rosai J (2017) WHO classification of tumours: pathology and genetics of tumours of endocrine organs, 4th edn. IARC, Lyon
Low KC, Tergaonkar V (2013) Telomerase: central regulator of all of the hallmarks of cancer. Trends Biochem Sci 38:426–434
McLeod DS, Sawka AM, Cooper DS (2013) Controversies in primary treatment of low-risk papillary thyroid cancer. Lancet 381:1046–1057
Nasirden A, Saito T, Fukumura Y, Hara K, Akaike K, Kurisaki-Arakawa A et al (2016) In Japanese patients with papillary thyroid carcinoma, TERT promoter mutation is associated with poor prognosis, in contrast to BRAF (V600E) mutation. Virchows Arch 469:687–696
Nikiforov YE, Nikiforova MN (2011) Molecular genetics and diagnosis of thyroid cancer. Nat Rev Endocrinol 7:569–580
Rachakonda PS, Hosen I, de Verdier PJ, Fallah M, Heidenreich B, Ryk C et al (2013) TERT promoter mutations in bladder cancer affect patient survival and disease recurrence through modification by a common polymorphism. Proc Natl Acad Sci USA 110:17426–17431
Roman BR, Morris LG, Davies L (2017) The thyroid cancer epidemic, 2017 perspective. Curr Opin Endocrinol Diabetes Obes 24:332–336
Siegel RL, Miller KD, Jemal A (2019) Cancer statistics, 2019. CA Cancer J Clin 69:7–34
Vinagre J, Almeida A, Populo H, Batista R, Lyra J, Pinto V et al (2013) Frequency of TERT promoter mutations in human cancers. Nat Commun 4:2185
Vuong HG, Altibi AMA, Duong UNP, Hassell L (2017) Prognostic implication of BRAF and TERT promoter mutation combination in papillary thyroid carcinoma-A meta-analysis. Clin Endocrinol (oxf) 87:411–417
Xing M, Westra WH, Tufano RP, Cohen Y, Rosenbaum E, Rhoden KJ et al (2005) BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. J Clin Endocrinol Metab 90:6373–6379
Xing M, Alzahrani AS, Carson KA, Viola D, Elisei R, Bendlova B et al (2013a) Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer. JAMA 309:1493–1501
Xing M, Haugen BR, Schlumberger M (2013b) Progress in molecular-based management of differentiated thyroid cancer. Lancet 381:1058–1069
Xing M, Liu R, Liu X, Murugan AK, Zhu G, Zeiger MA et al (2014) BRAF V600E and TERT promoter mutations cooperatively identify the most aggressive papillary thyroid cancer with highest recurrence. J Clin Oncol 32:2718–2726
Xing M, Alzahrani AS, Carson KA, Shong YK, Kim TY, Viola D et al (2015) Association between BRAF V600E mutation and recurrence of papillary thyroid cancer. J Clin Oncol 33:42–50
Funding
This work has been supported by National Nature Science Foundation of China (Grant No. 81972500, 81972543), Natural Science Foundation of Shandong Province, China (Grant No. ZR2019MH024), Grant from Innovation Program of Shanghai Science and technology committee (20Z11900304), Grant from Shanghai Clinical research key support project/ Science and Technology commission of Shanghai Municipality (SHDC2020CR6003-002), and Clinical research funds from Shanghai Jiao Tong University Affiliated Sixth People's Hospital (Zhiyan Liu).
Author information
Authors and Affiliations
Contributions
ZD and XT performed the experiments and wrote the paper. XD, BG, JK, BW, ZY, CC, PL and YZ acted as the assistants. YF and ZL were responsible for the design and for funding collection. All authors read and approved the final manuscript.
Ethics declarations
Conflict of interest
The authors declare they have no competing financial interests.
Ethical approval
This study was approved by the Ethics Committee of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, and all patients provided signed informed consent.
Consent for publication
All authors approve the publication of the manuscript.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Ding, Z., Tao, X., Deng, X. et al. Genetic analysis and clinicopathologic features of locally advanced papillary thyroid cancers: a prospective observational study. J Cancer Res Clin Oncol 149, 6303–6313 (2023). https://doi.org/10.1007/s00432-022-04541-w
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-022-04541-w