30 chapter 2 BRAFK601E point mutation A less common activating BRAF mutation is BRAFK601E (c.1801A>G), which occurs considerably less frequently than the BRAFV600E variant and is associated with FVPTC with high specificity [123]. Clinically, the characterization of a small cohort of thyroid malignancies with a BRAFK601E mutation showed better outcomes than for BRAFV600E mutated tumours: no extrathyroidal tumour extension, recurrence, lymph node or distant metastasis were reported in indeterminate BRAFK601E positive tumours with a median follow-up of 20 months (range 4-47) [124]. Availability, cost-effectiveness and limitations of BRAF mutation analysis Altogether, the consistent perfect specificity in a large number of studies supports the use of BRAF mutation analysis in obviating two-stage surgery. The technique is increasingly available in the clinical setting worldwide. A prior meta-analysis of eight studies questioned the cost-effectiveness of BRAFV600E mutation analysis in indeterminate thyroid nodules based on a mere 4.6% mean prevalence of the mutation [125]. Cost-effectiveness studies concerning sole BRAF mutation analysis in indeterminate thyroid nodules are lacking. Regardless, cost-effectiveness is generally presumed, as average costs for testing are relatively low and decreasing over time. Depending on the applied molecular technique, reported costs for BRAF mutation analysis ranged between €7.50 and $123 per tested sample [91, 101, 110, 126]. Low sensitivity remains the main limitation of BRAF mutation analysis, irrespective of the type of indeterminate cytology. Proficiency of the test in preoperative patient management depends on the regional occurrence rate of BRAF-mutated PTC; in South Korea, more patients will benefit from BRAF mutation analysis, and the probability and extent of cost-effectiveness are likely to increase [104]. In other health care systems, such as in the UK, cost-effectiveness is likely more constrained. Nonetheless, BRAF testing could still save approximately half the surgical costs in BRAF mutation-positive carcinoma [101, 103]. These global variations should be considered before local implementation of sole BRAF mutation analysis. RAS point mutation Point mutations in the gene family of retrovirus-associated DNA sequences (RAS) together constitute the second most frequently occurring genetic alteration in thyroid carcinoma. In indeterminate thyroid nodules, they are the most common genetic alteration, due to a strong association of RAS mutations with the follicular-patterned lesions that make up these cytological categories: follicular adenoma, FTC, FVPTC and noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) [41, 43, 69, 97, 127, 128]. Originally, two of the three homologous RAS genes were identified as viral genes of the oncogenic Harvey (HRAS) and Kirsten (KRAS) murine sarcoma virus; the third, NRAS,
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