31 Diagnostic utility of molecular and imaging biomarkers 2 was first identified in neuroblastoma cells [129, 130]. The genes code for GTP-binding RAS proteins, which are involved in intracellular signalling in the MAPK/ERK pathway. Mutation causes overactive RAS signalling and could ultimately induce malignant transition [64]. RAS mutation in thyroid carcinoma has been associated with favourable prognostic factors, such as encapsulation of the tumour and absence of lymph node metastases, but also with factors indicative of an adverse prognosis, such as poor cell differentiation [42]. RAS mutations are not specific for carcinoma and found in both malignant and benign lesions [69, 99, 128]. According to the 2015 ATA guidelines, Bethesda III or IV nodules with a RAS mutation should be treated similar to the Bethesda V category, as approximately 4 out of 5 are malignant [17, 44]. HRAS, KRAS and NRAS mutations are mutually exclusive. They are each associated with slightly different types of cytology and histology, and consequently a different clinical course. In general, point mutations in NRAS codon 61 and HRAS codon 61 are said to occur most frequently [43, 102]. KRAS is associated with oncocytic lesions and a lower malignancy rate than other RAS mutations [131]. A RAS point mutation is found in 0% to 38% of the indeterminate nodules [77, 98]. Moreover, approximately a third of all reported malignancies resulting from indeterminate thyroid cytology are RAS mutation positive, frequently FVPTC or FTC [69, 75-77, 114]. Sporadic cases of RAS mutationpositive FTC-OV and MTC are reported [75, 76]. In individual studies, sensitivity and specificity of RAS mutation analysis ranged from 0% to 77% and from 75% to 100%, respectively [77, 98, 128]. Test performance was similar for Bethesda III and IV categories, although the mutation occurred more frequently in Bethesda IV nodules [60, 67, 69, 77, 88, 97, 98, 114, 118, 128]. Histopathologically benign nodules carrying a RAS mutation are histopathological follicular adenoma in most cases, but also oncocytic variant of follicular adenoma (Hürthle cell adenoma) or hyperplastic nodules [67, 69, 76, 88, 128]. There is an ongoing discussion regarding the interpretation of a false positive RAS mutation. It is presumed that an oncogenic RAS mutation predisposes a follicular adenoma for progression into follicular carcinoma – a RAS-mutated follicular adenoma should be considered a premalignant pre-invasive follicular neoplasm. These assumptions put false-positives in a different light, as it would justify resection of such lesions through hemithyroidectomy. Consequently, the lesions could also be considered true-positives – improving the specificity of RAS mutation analysis [41, 60, 77, 97, 99, 109]. However, the exact mechanisms behind the malignant potential and transition for RAS-mutated follicular adenomas are not yet clarified and difficult to appreciate in a clinical setting. Similar to BRAF, there was evident global variation in the distribution of RAS mutations. Many European and American studies reported a clear predominance of RAS mutations over BRAF mutations. Solely a Brazilian study of 116 Bethesda III and 20 Bethesda IV thyroid nodules reported only BRAF mutations and not a single RAS mutation [98]. The previously described predominance of BRAF mutations in South Korean populations was confirmed in the sole study that investigated both point mutations in one population [77]. Combined BRAF/RAS mutation analysis could be considered, although geographical differences in the distribution of the two genetic alterations strongly influence feasibility. A gene mutation panel consisting of more genetic alterations (discussed in a
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