BRAF (p.V600E) mutation has been associated in many studies with the aggressiveness of PTC (extrathyroidal invasion, lymph node metastasis and advanced stage) and also with disease specific mortality when associated with other aggressive features, such as extrathyroidal growth. BRAF mutation offers a very low positive predictive value (28%) and a high negative predictive value (87%) for disease recurrence, therefore suggesting that BRAF mutation in the clinical management of PTC should be used with caution. BRAF mutation also has been associated with the loss of radioactive iodine avidity of recurrent PTC.

RAS mutations are associated with a thyroid neoplasm with a follicular pattern, and have also been reported in poorly DTC. The clinical significance of RAS mutations in thyroid cancer is controversial. Some reports show that RAS mutations are associated with tumor aggressive phenotypes and poor prognosis, while others could not confirm this association.

Similarly, RET/PTC rearrangements were associated in some reports with lymph node metastasis and extrathyroidal extension, and with a better prognosis in other studies.

PAX8-PPARG rearrangements have been associated with multifocality of the tumors and vascular invasion, conferring an invasive potential. Despite this, the consistent detection of PAX8-PPARG rearrangements in benign tumors hinders its value as a diagnostic molecular marker.

To date, none of these markers have been demonstrated to be clear, ""independent"" prognostic indicators, thus preventing their widespread acceptance and utilization in clinical practice.

The BRAF gene mutated nell'FNC is diagnostic in papillary carcinomas that express the BRAF gene.

RTK (receptor tyrosine kinase), Ras/Raf (MAPK), PI3K mutations are common in both papillary and follicular cancers. To my understanding based on molecular mechanisms, loss of normal signaling mechanisms (e.g.,TSHR/ Gs-alpha G protein or cAMP/PKA/CREB/PAX8/TTF-1 signaling cascades for thyrocytes and others in papillary) is a key to understand their nature or invasiveness. Ras/Raf or RTK seems to be more invasive as both use the sam pathway, RTK can also activate AKT pathway, so it would be difficult to judge invasiveness by looking at only one type of mutations, I would recommend to test all these cheek-points to determine the invasiveness status then to make sure which of them give the worst results further to confirm future investigations.

BRAF V600E mutations in thyroid tumors are distinct findings in papillary thyroid cancer, which vary between 20%->70%. Mutation positive findings are associated with factors predicting worse prognosis in PTC but is of questionable importance by itself. Thus PTCs in older patients, with clinical evident lymph node metastasis and increased TNM stage show a higher incidence of BRAF muations than i.e. micro PTC (PTMC). The variation of BRAF V600E mutation between subgroups of PTC (classic, follicular, tall cell variant etc.) and between different countries differs considerably, making it altogether impossible to draw a definite conclusion on the importance of BRAF mutation on PTC prognosis in humans.

For diagnostic reasons, however, mutation analysis can be valuable when cytologically questionable thyroid nodules are assessed, because BRAF mutation V600E has not been demonstrated in follicular adenomas and benign nodular goiters but neither in follicular thyroid carcinomas (FTC). Thus only a positive finding predicts a PTC, whereas a negative finding does not exclude PTC or FTC.

Therefore the question is pending, whether this genetic analysis of mutations in oncogenes and tumor suppressor genes or the differential expression profile of genes expressed in thyrocytes may be more helpful in separating benign from maligant thyroid tumors.

This is an interesting question and an actual matter of debate but to my mind, there is no contradiction between these 2 assertions.

BRAF mutation is present in around 40% of papillary thyroid carcinomas and never in benign lesions. In patients with thyroid nodules, FNA spécimens give an indeterminate result in 20 to 30% of cases and these patients are often operated although the lesion is benign in most cases. It is, thus, important to improve the performances of FNA. BRAF determination on FNA specimens may contribute since when a BRAF mutation is identified, this ensures the diagnosis of PTC. By contrast, when the analysis is negative, a cancer cannot be ruled out. Research is, now, focusing on the identification of molecular sets allowing better discrimination between malignant and benign diseases.

Papillary thyroid carcinomas are usually of good prognosis with an overall survival of 95% at 10 years but it is estimated that 3 to 5% of patients die from their cancer and that 10 to 20% have a recurence. There is a debate on the prognosis value of BRAF mutation. It has been reported that thyroid cancer with a BRAF mutation are more agressive, with frequent extra-thyroidal extension and FDG PET avide lesions. However the impact of BRAF status on patient's outcome is not fully determined. Moreover, it is not demonstrated that extensive lymph-node dissection improves post-operative outcome in such patients.

This is an active research field and more definite responses are expected in the next few years

to my opinion, the role of BRAF is exaggerated and more likely it is age-related or age-dependent event. in the long run it does not influence clinical features or metastatic tumor response to radio-iodine treatment. see, for example, long -term results of treatment of childhood papillary thyroid carcinomas and papers that discussed mortality in older aged patients

My first opinion on Role of Braf.... :

1) The overall outcome on patients with papillary carcinoma is excellent. The V600 BRAF mutation is positive in nearly 70 % papillary carcinoma, therefore showing that most PTCs, with BRAF mutation are not aggressive. It is clearly wrong to suggest that this mutation should be considered as a poor prognostic marker in PTC. That BRAF mutant PTCs also include those that are aggressive does not mean that the PTCs with the BRAF mutation have a poor prognosis. In conclusion, there is a misconception among pathologists and clinicians, who believe that BRAF positive means aggressive. It does not. If there was a correlation between prognosis and BRAF mutation, considering that nearly 70 %

of papillary carcinomas have V600-BRAF mutation, we would have the 70/80 % of papillary carcinomas with poor prognosis, but we do not.

My second Opinion:

Finally, BRAF as a target for new therapies to treathigh-risk patients with recurrent or metastatic disease who have exhausted conventional therapies holds exciting

promise.