Trends in Endocrinology & Metabolism
ReviewClinical implications of BRAF mutation in thyroid carcinoma
Section snippets
BRAF mutation as a potential new clinical tool for thyroid cancer
Thyroid cancer, the most common endocrine malignancy, represents ∼1% of all malignancies in Western countries [1]. It is the cancer with the most rapidly increasing incidence rates in women and the second most rapid in men. With an annual percentage change of ∼5%, it is now the sixth most common cancer in women [2].
Over 80% of malignant thyroid tumors are papillary carcinomas [1]. Significant progress has been made in the clinical management of papillary thyroid cancer (PTC) [3] but there is
The molecular epidemiology of BRAF mutations in PTC
Raf (see Glossary) is a serine/threonine-selective protein kinase involved in the mitogen-activated protein kinase (MAPK) pathway [6] (Figure 1), whose constitutive activation leads to tumorigenesis. Of the three functional Raf isoforms described in humans, the most potent MAPK pathway activator is BRAF, which is encoded by a gene on chromosome 7 and is expressed in all cell types [6]. Large-scale genomic screens have detected BRAF mutations in 66% of all malignant melanomas and in some
Diagnostic relevance of BRAF mutations in thyroid lesion work-up
Fine-needle aspiration cytology (FNAC) is the most sensitive and specific method for identifying malignant thyroid nodules. In specialized centers, its diagnostic accuracy approaches 98%, with false-positive and false-negative rates of <2% [25]. However, 15% of thyroid nodule FNAs prove to be inadequate for cytological diagnosis, and in another 10% (generally involving follicular or Hürthle cell tumors), it is not possible to determine with certainty whether the nodule is an adenoma or
Prognostic significance of BRAF mutations
Prognostic characterization of PTCs is important for decisions regarding the initial treatment (e.g. surgery, with or without radioiodine ablation) and the aggressiveness of follow-up. The individual risk for tumor recurrence is conventionally evaluated based on age at diagnosis, tumor histology, tumor extension and the completeness of the surgical resection. One evident drawback of this routine is that it precludes full risk assessment at the preoperative phase. In addition, predictions based
BRAF as a therapeutic target in PTC
Targeted therapies for cancer tend to be most effective when the therapeutic compound inhibits a pathway that is constitutively activated during the early stages of tumor development, as is the case for the Raf–MAPK kinase (MEK)–ERK cascade in PTC 14, 53. Because the BRAF mutation predicts tumor sensitivity to MEK inhibition [54], selective inhibitors of BRAF kinase or its direct downstream effectors are logical candidates for the treatment of advanced PTCs [55]. Preclinical data support the
Conclusions and perspectives
Currently available data suggest potential roles for BRAF mutation testing in the management of PTC, although its field of application awaits further definition. BRAF mutation analysis of FNA specimens could theoretically help to distinguish between benign and malignant tumors when cytology is inconclusive. Unfortunately, inconclusive cytology generally arises with follicular neoplasms, which are not associated with BRAF mutations, or follicular PTC variants, in which BRAF mutations are rare.
Acknowledgements
This work was supported by grants from the Italian Ministry of Universities and Research (COFIN), the Italian Ministry of Health (Grant Ricerca Finalizzata – 2004) and the Italian Association for Cancer Research (AIRC) (to S. F.). Support was also received from the ‘Fondazione Umberto Di Mario ONLUS’ (to S.F.), from the “Banca d’Italia” (to S.F.) and from the ‘Fondazione Cassa di Risparmio di Perugia’ (to E.P.). C.D. is a PhD Fellow in the ’Endocrinology and Molecular Medicine’ Program at the
Glossary
- Allele-specific LightCycler PCR
- allele-specific LightCycler PCR is a mutation screening technique used to detect nucleotide point mutations. It is based on the ability of Real-Time LightCycler® Instruments to monitor the melting points of probes based on decreases in fluorescence. Higher melting points are indicative of more stable hybridization (binding) between the probe and its target. Mutations [e.g., single nucleotide polymorphisms (SNPs)] weaken probe binding and can easily be recognized.
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MiR-let-7e inhibits invasion and magration and regulates HMGB1 expression in papillary thyroid carcinoma
2019, Biomedicine and PharmacotherapyCitation Excerpt :and approximately 10 percent patients dedifferentiate into deadlier thyroid cancers [7–9]. Although many studies have identified a few genes that are involved in the progression of this malignancy, the pathogenesis of PTC remains to be elucidated [10]. Many studies suggested that microRNAs are associated with aggressive clinic pathologic features in PTC and may be the useful prognostic markers [11–14].
Targeting post-translational histone modifications for the treatment of non-medullary thyroid cancer
2018, Molecular and Cellular EndocrinologyCitation Excerpt :The high success rate of radioactive iodine-based therapy in iodide-concentrating DTCs (Durante et al., 2006) has encouraged efforts to restore this function in tumor cells in which thyroid-specific proteins—mainly sodium/iodide symporter (NIS) and thyroperoxidase (TPO)—are not expressed or are nonfunctional (Arturi et al., 2000; Schlumberger et al., 2007; Hou et al., 2010). Since the oncogenic alterations that de-regulate thyroid cell proliferation are also responsible for loss of differentiation in transformed thyrocytes (Trapasso et al., 1999; Puxeddu et al., 2008; Xing, 2013), TKI have been successfully used (Bernet and Smallridge, 2014; Omur and Baran, 2014; Fallahi et al., 2015; Bulotta et al., 2016) It has recently been reported that oncogene-activated signaling pathways in thyroid cancer cells control post-translational histone modifications on thyroid-specific genes (D'Agostino et al., 2014). This finding supports attempts to reverse the de-differentiation of malignant thyroid cells using modulators of histone acetylation/deacetylation.
The role of miRNAs in the evaluation of follicular thyroid neoplasms: an overview of literature
2017, Journal of the American Society of CytopathologyCitation Excerpt :Although the morphologic diagnosis of either the 70% benign and the 5% to 10% “malignant” thyroid FNACs has been achieved in the majority of cases, the remaining 20% to 25% of them represents the so-called gray zone of FNs, implying vexing issue in both their nature and the consequent management (clinical and/or surgical).1-15 Thus, several authors have questioned whether the application of ancillary techniques (including immunocytochemistry and molecular tests) would increase the accuracy of cytology in detecting malignant cases among the indeterminate categories, mostly due to the high negative predictive value.16-35 Despite the undoubted advantages of the detection of somatic mutations and rearrangements provided by all the different DNA molecular platforms, however, these authors did not supply 100% of the achievements, especially for the diagnosis of FNs.16-35
Fibronectin-1 expression is increased in aggressive thyroid cancer and favors the migration and invasion of cancer cells
2016, Molecular and Cellular EndocrinologyCitation Excerpt :Subsequently, another EMT marker, periostin, was reported to be overexpressed in PTC, and its mRNA levels were positively correlated with extrathyroidal invasion, distant metastasis, and higher grade staging (Puppin et al., 2008). Interestingly, ECM alterations have been described as a consequence of the BRAFV600E mutation (Nucera et al., 2011), the most common genetic alteration detected in human PTCs, and increasing bodies of in vitro and in vivo data suggest that this mutation is associated with invasive properties and aggressive behavior in thyroid cancer (Durante et al., 2007; Puxeddu et al., 2008; Nucera et al., 2009; Knauf et al., 2011). In this study, we investigated the gene expression levels of 27 EMT markers in group of 36 PTCs classified as intermediate or low risk (IR or LR) tumors according to current criteria published by the American Thyroid Association (ATA) (Haugen et al., 2016).