Multiple Mutations Detected Preoperatively May Predict Aggressive Behavior of Papillary Thyroid Cancer and Guide Management—A Case Report

Shrestha, Rupendra T.; Karunamurthy, Arivarasan; Amin, Khalid; Nikiforov, Yuri E.; Caramori, M. L.

doi:10.1089/thy.2015.0278

Cited by 26 publications

(20 citation statements)

References 14 publications

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“…These clinicopathological data strongly support a prominent role of TERT promoter mutations in the tumorigenesis and progression of thyroid cancer, which is well corroborated by previous results on similar differential expression patterns of TERT in benign and malignant thyroid tumors. As such, TERT promoter mutations are promising diagnostic and prognostic genetic markers for thyroid cancer, which is highly applicable clinically as demonstrated recently by applying them to thyroid fine needle aspiration biopsy for such purposes (Liu & Xing 2014; Nikiforov et al 2014; Shrestha et al 2015). Future studies will need to more specifically define such clinical utilities, elucidate the biological mechanisms of the role of TERT promoter mutations in thyroid tumorigenesis, and explore and establish the therapeutic utilities of targeting TERT for thyroid cancer.…”

Section: Discussionmentioning

confidence: 99%

TERT promoter mutations in thyroid cancer

Liu¹,

Xing²

2016

Endocrine-Related Cancer

343

301

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The 2013 discovery of TERT promoter mutations chr5, 1,295,228 C>T (C228T) and 1,295,250 C>T (C250T) in thyroid cancer represents an important event in the thyroid cancer field and much progress has occurred since then. This article provides a comprehensive review of this exciting new thyroid cancer field. The oncogenic role of TERT promoter mutations involves their creation of consensus binding sites for ETS transcriptional factors. TERT C228T is far more common than TERT C250T and their collective prevalence is, on average, 0%, 11.3%, 17.1%, 43.2%, and 40.1% in benign thyroid tumors, papillary thyroid cancer (PTC), follicular thyroid cancer, poorly differentiated thyroid cancer, and anaplastic thyroid cancer, respectively, displaying an association with aggressive types of thyroid cancer. TERT promoter mutations are associated with aggressive thyroid tumor characteristics, tumor recurrence, and patient mortality as well as BRAF V600E mutation. Coexisting BRAF V600E and TERT promoter mutations have a robust synergistic impact on the aggressiveness of PTC, including a sharply increased tumor recurrence and patient mortality, while either mutation alone has a modest impact. Thus, TERT with promoter mutations represents a prominent new oncogene in thyroid cancer and the mutations are promising new diagnostic and prognostic genetic markers for thyroid cancer, which, in combination with BRAF V600E mutation or other genetic markers (e.g., RAS mutations), are proving to be clinically useful for the management of thyroid cancer. Future studies will specifically define such clinical utilities, elucidate the biological mechanisms, and explore the potential as therapeutic targets of TERT promoter mutations in thyroid cancer.

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Section: Discussionmentioning

confidence: 99%

TERT promoter mutations in thyroid cancer

Liu¹,

Xing²

2016

Endocrine-Related Cancer

343

301

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“…Most WDTC have indolent behavior, and the early identification of high-risk patients who may exhibit a more aggressive course of the disease is important in order to try to find a way of preventing unfavorable developments [Shrestha et al, 2015].…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have shown the feasibility of mutational analysis in fine needle biopsy aspirates [Xing et al, 2014;Shrestha et al, 2015;Crescenzi et al, 2016] allowing preoperatively to evaluate the mutational tumor profile. The benefits of this approach are evident, for example, in undetermined cytology specimens in which the identification of a BRAF V600E mutation is almost 100% diagnostic of PTC.…”

Section: Discussionmentioning

confidence: 99%

“…In the TCGA study, which involved 400 patients with PTC, only 3 (0.8%) were shown to have an AKT1 mutation and 2 (0.5%) a PIK3CA mutation [Cancer Genome Atlas Research Network, 2014;Shrestha et al, 2015]. None of the aforementioned PTC had simultaneous occurrence of BRAF mutations with AKT1 and PIK3CA mutation, showing that multiple mutations are rare in PTC and, when they occur, BRAF and PIK3CA or AKT1 are found in more advanced tumors, less differentiated, and refractory to iodine [Ricarte-Filho et al, 2009;Nikiforova et al, 2013].…”

Section: Braf Mutations In Tcdfcmentioning

confidence: 99%

“…Of the patients who relapse, 5-10% do not respond to conventional therapies and may die from the disease. Since most of the WDTC have an indolent behavior, early identification of high-risk patients who will probably have a more aggressive disease is important in order to find a way to prevent the negative evolution of the disease [Shrestha et al, 2015]. The challenge is how to identify patients requiring more aggressive treatment while, at the same time, preserving the majority of the patients from unnecessary treatments and procedures [Esserman et al, 2013;Rosario et al, 2013].…”

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confidence: 99%

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Molecular Markers Involved in Tumorigenesis of Thyroid Carcinoma: Focus on Aggressive Histotypes

Penna

Vaisman

et al. 2016

Cytogenet Genome Res

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Thyroid cancer derived from follicular cells (TCDFC) comprises well-differentiated (papillary and follicular) carcinoma, poorly differentiated carcinoma, and anaplastic carcinoma. Papillary thyroid carcinoma is the most common endocrine cancer, and its incidence is steadily increasing. Lethality and aggressiveness of TCDFC is inversely correlated with differentiation degree. In this review, an emphasis has been put on molecular markers involved in tumorigenesis of thyroid carcinoma with a focus on aggressive histotypes and the role of such biomarkers in predicting thyroid cancer outcome. Genetic rearrangements in TCDFC (RET/PTC, PAX8/PPARG) and mutations in RAS, BRAF, TERT promoter (TERTp), TP53, PIK3CA, and AKT1 are discussed. The majority of the studies to date indicate that TERTp mutations can serve as a marker of more aggressive disease in all the subtypes of thyroid carcinoma, being the best current marker of poor prognosis, due to its independent association with distant metastases and increased disease-specific mortality. Some studies suggested that a more accurate prediction of thyroid cancer outcome may be possible through a more extensive genetic analysis. The same is true concerning the identification of other mutations that are only relatively frequent in advanced tumors (e.g., TP53, PIK3CA, or AKT1). A better understanding of the prognostic role of TERTp mutation (together with additional ones like BRAF, RAS, PIK3CA, AKT1, or TP53) and the clarification of their putative role in fine-needle aspiration biopsies are likely to allow, in the future, an early refinement of the stratification risk in patients with well-differentiated carcinomas. It is worth noting that, as with any categorical staging system, the risk evaluation within each category (low, intermediate, and high) varies depending on the specific clinicopathologic features of individual patients and the specific biological behavior of the tumor. Finally, besides the diagnostic and/or prognostic significance of the above-mentioned mutations, it is crucial to understand that the molecular pathways and epigenetic alterations will likely turn into interesting targets for new therapies.

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