28 chapter 2 Molecular biomarkers Gene mutation analysis and gene expression In the last decades, researchers have unravelled important molecular mechanisms behind the thyroid tumorigenesis, and designated a great number of genetic alterations that are related to the various types of thyroid carcinoma. Several of these mutational markers have found their way to the preoperative diagnosis of indeterminate thyroid nodules. The most common markers are the somatic BRAF and RAS point mutations, and RET/PTC rearrangement, all of which involve the mitogen-activated protein kinase (MAPK) signalling pathway [62-64]. In the 2015 ATA guidelines the potentially strong diagnostic impact of molecular testing is explicitly unfolded, focusing on BRAF testing and the – at that date – two main commercially available tests: the seven-gene mutation panel miRInform® thyroid (Asuragen Inc., Austin, Texas) and the Afirma® gene expression classifier (Veracyte, Inc., South San Francisco, CA). The ATA recommends considerate application of one of these molecular tests for Bethesda III and IV nodules, provided that the result could change the treatment strategy [17]. In the following chapters, the diagnostic potential of mutation analysis in indeterminate thyroid nodules is discussed, including the tests mentioned in the guidelines as well as other individual molecular biomarkers and multi-gene panels addressed in literature. BRAF mutation B-type RAF kinase (BRAF) is a serine–threonine kinase belonging to the rapidly accelerated fibrosarcoma (RAF) family, and the most potent mitogen-activated protein kinase (MAPK) pathway activator. Point mutations in the BRAF proto-oncogene occur in various human cancers. The somatic BRAFV600E mutation is the most common activating mutation in many carcinomas, including thyroid carcinoma [62]. This missense mutation consists of a thymine-to-adenine substitution at nucleotide 1799 (c.1799T>A), resulting in an amino acid substitution where valine is replaced with glutamate at codon 600 (hence V600E)[65, 66]. BRAF has an important function in cell proliferation, differentiation, and apoptosis. Upregulation of BRAF through the BRAFV600E activating mutation is associated with tumorigenesis [66]. In differentiated thyroid cancer, the BRAFV600E mutation is exclusive to PTC, occurring in 50% to 80% of these tumours [62, 63, 67-77]. The BRAFV600E mutation has been prognostically associated with poor clinicopathological outcomes, such as increased incidence of extrathyroidal invasion, recurrence of disease, and distant metastasis of the tumour [78-80].
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