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

Abstract

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.

Differentiated Thyroid Cancer—Treatment: State of the Art

“…The role of RAS is discussed controversally. Table 2 shows the impact of the two well-evaluated molecular markers BRAF and TERT [15]. Some of these alterations might be interesting molecular targets for new therapies.…”

“…Numerous molecular tests can be applied to distinguish malignant from benign lesions, such as BRAF (V600E), PIK3CA and TERT promoter, AKT1, and TP53, although there is no explicit recommendation in the current guidelines. Accordingly, adjustments are to be expected in the future [15]. For more non-diagnostic biopsies in a row, the decision for close surveillance without intervention or for surgery should be made in dependence of the sonographic pattern [10].…”

Targeted next‑generation sequencing of cancer‑related genes in thyroid carcinoma: A single institution's experience

“…TVPC, a subtype of PC, is characterized by a predominance of tall and oncocytic tumor cells. Patients with TVPC exhibit a higher recurrence rate and decreased disease-specific survival (56). The BRAF V600E mutation is reportedly common in approximately 80% of TVPC cases (4).…”

Spectrum of TERT promoter mutations and mechanisms of activation in thyroid cancer

“…The majority of thyroid tumors arise from thyroid follicular cells, comprising well‐differentiated thyroid papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC), poorly differentiated thyroid carcinoma (PDTC) and anaplastic (undifferentiated) thyroid carcinoma (ATC) . Initiation and progression of thyroid cancer occur through gradual accumulation of early and late genetic and epigenetic events, which lead to the activation of the MAPK and PI3K‐AKT signaling pathways . Early genetic events in thyroid cancer progression (ie, BRAF mutations) are frequently found in both well‐differentiated thyroid cancer and in PDTC or ATC, therefore they are involved in tumor initiation and in the predisposition of the tumor to dedifferentiation.…”