TERT promoter mutations in thyroid cancers
Iñigo Landa, PhD
Brigham and Women’s Hospital & Harvard Medical School
May 20, 2022
Thyroid cancers are driven by a handful of genetic alterations. Papillary thyroid cancer (PTC), the most frequent thyroid tumor with excellent survival rates, primarily harbors mutations involving BRAF, RAS or RET genes, which in turn constitutively activate the MAPK pathway, a key process for cell proliferation (1). A subset of PTCs can evolve to more aggressive forms, namely poorly differentiated (PDTC) and anaplastic thyroid cancers (ATC), which account for most of the disease-associated morbidity and mortality (2, 3). TERT (telomerase reverse transcriptase) is one of the genes that is most often mutated as thyroid cancer progresses. Mutations in TERT occur in its promoter region, which is the non-coding portion of a gene acting as an on/off switch. The acquisition of a TERT promoter mutation (TPM) reactivates the expression of telomerase, a bona fide oncogene that is otherwise silenced in human adult cells.
TPMs were discovered in advanced melanomas in 2013 (4, 5), then found at high rates in certain tumor types, such as glioblastomas, bladder and hepatocellular carcinomas (6), and shortly after reported in thyroid carcinomas (7-10). Remarkably, TPMs display a stepwise increase across thyroid specimens, tracking with tumor virulence. Less than 10% of the mostly indolent PTCs harbor TPMs; this prevalence increases in high grade PTCs and PDTCs, rising to more than 70% in the highly aggressive ATCs (11-13). Within each tumor type, TPMs systematically associate with poor prognosis. They correlate with an increased frequency of metastasis, persistent disease and lower survival in PTC patients, particularly when they co- occur with BRAFV600E or RAS oncogenic mutations (14-16). In advanced disease, patients with TERT-mutant PDTCs develop more metastasis, whereas survival of ATC patients whose tumors carry TPMs is further diminished (12). Overall, TERT promoter mutations have become a promising biomarker of poor prognosis which is progressively being incorporated in the guidelines for the management of thyroid cancer patients (17, 18).
Telomerase reactivation, which in thyroid tumors mainly occur via the acquisition of TPMs, likely enhances several molecular functions of TERT, which are relevant for the biology of cancer cells. The best-known role of telomerase is its ability to prevent the critical shortening of chromosomal ends (called “telomeres”), thus circumventing the molecular clock for cells to stop dividing (19). There are, however, multiple non-telomeric TERT functions that likely favor cancer fitness (20, 21). The elucidation of which of these cellular processes are unleashed in aggressive thyroid tumors is a topic of great interest for research, and has the potential to unveil novel nodes for genotype-driven and mechanism-oriented therapeutic intervention for thyroid cancer patients harboring TPMs.
1. Fagin JA, and Wells SA, Jr. Biologic and Clinical Perspectives on Thyroid Cancer. N Engl J Med. 2016;375(23):2307.
2. Nikiforov YE, and Nikiforova MN. Molecular genetics and diagnosis of thyroid cancer. Nat Rev Endocrinol. 2011;7(10):569-80.
3. Smallridge RC, and Copland JA. Anaplastic thyroid carcinoma: pathogenesis and emerging therapies. Clin Oncol (R Coll Radiol). 2010;22(6):486-97.
4. Huang FW, Hodis E, Xu MJ, Kryukov GV, Chin L, and Garraway LA. Highly recurrent TERT promoter mutations in human melanoma. Science. 2013;339(6122):957-9.
5. Horn S, Figl A, Rachakonda PS, Fischer C, Sucker A, Gast A, et al. TERT promoter mutations in familial and sporadic melanoma. Science. 2013;339(6122):959-61.
6. Killela PJ, Reitman ZJ, Jiao Y, Bettegowda C, Agrawal N, Diaz LA, Jr., et al. 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 U S A. 2013;110(15):6021-6.
7. Landa I, Ganly I, Chan TA, Mitsutake N, Matsuse M, Ibrahimpasic T, et al. Frequent somatic TERT promoter mutations in thyroid cancer: higher prevalence in advanced forms of the disease. J Clin Endocrinol Metab. 2013;98(9):E1562-6.
8. Liu T, Wang N, Cao J, Sofiadis A, Dinets A, Zedenius J, et al. The age- and shorter telomere-dependent TERT promoter mutation in follicular thyroid cell-derived carcinomas. Oncogene. 2013.
9. Liu X, Bishop J, Shan Y, Pai S, Liu D, Murugan AK, et al. Highly prevalent TERT promoter mutations in aggressive thyroid cancers. Endocr Relat Cancer. 2013;20(4):603-10.
10. Vinagre J, Almeida A, Populo H, Batista R, Lyra J, Pinto V, et al. Frequency of TERT promoter mutations in human cancers. Nature communications. 2013;4:2185.
11. Cancer Genome Atlas Research N. Integrated genomic characterization of papillary thyroid carcinoma. Cell. 2014;159(3):676-90.
12. Landa I, Ibrahimpasic T, Boucai L, Sinha R, Knauf JA, Shah RH, et al. Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers. J Clin Invest. 2016;126(3):1052-66.
13. Pozdeyev N, Gay L, Sokol ES, Hartmaier RJ, Deaver KE, Davis SN, et al. Genetic analysis of 779 advanced differentiated and anaplastic thyroid cancers. Clin Cancer Res. 2018.
14. Melo M, Rocha AG, Vinagre J, Batista R, Peixoto J, Tavares C, et al. TERT promoter mutations are a major indicator of poor outcome in differentiated thyroid carcinomas. J Clin Endocrinol Metab. 2014:jc20133734.
15. Xing M, Liu R, Liu X, Murugan AK, Zhu G, Zeiger MA, et al. BRAF V600E and TERT promoter mutations cooperatively identify the most aggressive papillary thyroid cancer with highest recurrence. J Clin Oncol. 2014;32(25):2718-26.
16. Song YS, Lim JA, Choi H, Won JK, Moon JH, Cho SW, et al. Prognostic effects of TERT promoter mutations are enhanced by coexistence with BRAF or RAS mutations and strengthen the risk prediction by the ATA or TNM staging system in differentiated thyroid cancer patients. Cancer. 2016;122(9):1370-9.
17. Bible KC, Kebebew E, Brierley J, Brito JP, Cabanillas ME, Clark TJ, Jr., et al. 2021 American Thyroid Association Guidelines for Management of Patients with Anaplastic Thyroid Cancer. Thyroid. 2021;31(3):337-86.
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