Application of molecular biology of differentiated thyroid cancer for clinical prognostication

Abstract

Although cancer outcome results from the interplay between genetics and environment, researchers are making a great effort for applying molecular biology in the prognostication of differentiated thyroid cancer (DTC). Nevertheless, role of molecular characterisation in the prognostic setting of DTC is still nebulous. Among the most common and well-characterised genetic alterations related to DTC, including mutations of BRAF and RAS and RET rearrangements, BRAF V600E is the only mutation showing unequivocal association with clinical outcome. Unfortunately, its accuracy is strongly limited by low specificity. Recently, the introduction of next-generation sequencing techniques led to the identification of TERT promoter and TP53 mutations in DTC. These genetic abnormalities may identify a small subgroup of tumours with highly aggressive behaviour, thus improving specificity of molecular prognostication. Although knowledge of prognostic significance of TP53 mutations is still anecdotal, mutations of the TERT promoter have showed clear association with clinical outcome. Nevertheless, this genetic marker needs to be analysed according to a multigenetic model, as its prognostic effect becomes negligible when present in isolation. Given that any genetic alteration has demonstrated, taken alone, enough specificity, the co-occurrence of driving mutations is emerging as an independent genetic signature of aggressiveness, with possible future application in clinical practice. DTC prognostication may be empowered in the near future by non-tissue molecular prognosticators, including circulating BRAF V600E and miRNAs. Although promising, use of these markers needs to be refined by the technical sight, and the actual prognostic value is still yet to be validated. 23:11Review V Marotta et al. Molecular prognosis in thyroid cancer

Precise Detection of Gene Mutations in Fine-Needle Aspiration Specimens of the Papillary Thyroid Microcarcinoma Using Next-Generation Sequencing

“…The BRAF mutation, confirmed as the most common driver mutational event involved in PTC [6, 7], has been identified as a highly specific marker of thyroid cancer as the mutation occurs exclusively in thyroid malignancy rather than in benignancy [8, 9]. In addition to the BRAF mutation, point mutations of the RAS gene, including NRAS, HRAS, and KRAS isoforms [6], represent the second most common genetic alterations in PTC [10]. In recent years, studies have found that TERT promoter mutations are emerging as a feasible tool for thyroid molecular prognostication [11, 12].…”

“…In recent years, studies have found that TERT promoter mutations are emerging as a feasible tool for thyroid molecular prognostication [11, 12]. Moreover, TP53 mutations may also act as a prognostic marker because it is typically considered a marker of tumor differentiation [6, 10]. In more in-depth molecular studies of PTMC, a correlation between BRAF and/or TERT promoter mutations and high-risk clinicopathological features of the lesion were described [13, 14].…”

Preoperative detection of TERT promoter and BRAFV600E mutations in papillary thyroid carcinoma in high-risk thyroid nodules

“…In recent years, molecularly established prognostication for PTC has been broadly advised (2)(3)(4). The role of BRAF V600Emutation test in bettering the preoperative premonition of thyroid nodules US guided fine-needle aspiration (FNA) is dubious in terms of the prognostic accuracy of BRAF V600E mutations in PTC (5,6).…”

A retrospective analysis of efficacy of systemic therapy in metastatic thyroid cancer

“…When considering all age groups, average incidence of thyroid cancer is 6.5% in women and 5.4% in men [1]. In general, about 75% of malignant thyroid tumours are presented as papillary thyroid cancer and 13% as follicular thyroid cancer, while the other types of thyroid cancer occur as medullary thyroid cancer by 7-8%, and to a lesser extent, as anaplastic (undifferentiated) thyroid cancer [2]. Recently, there have been some changes in the incidence order of thyroid cancer and particularly, micropapillary variant has been started to be observed more commonly [3].…”