Time to re‐consider the meaning of BRAF V600E mutation in papillary thyroid carcinoma

Abstract

The BRAF V600E mutation, resulting from the BRAFT1799A transversion, is the most common genetic mutation in papillary thyroid carcinoma (PTC), with a mean frequency close to 50% among all cases. A large number of studies in the past decade have tried to dissect the relevance and the function of the V600E mutation in controlling oncogenesis and progression of thyroid cancer. However, several works published in the latest years have provided new evidence, in partial conflict with the previous knowledge, suggesting the need of reconsidering the meaning of the BRAF V600E mutation in PTC. In this work, we attempt to discuss some of the most recent molecular, preclinical and clinical evidence to construct a more exhaustive model of function for the BRAF V600E in development, progression and therapeutic approach of thyroid cancer.In the past 10 years, a great interest has developed around the biological function of the BRAF V600E mutation in driving cancers. This mutation and its association with different clinical features have been largely investigated in different tumor settings and in particular in melanoma, colon cancer and thyroid carcinoma (Fig. 1). [1][2][3][4][5][6][7][8][9][10] In the field of thyroid oncology, the BRAF mutation is synonymous of malignancy, since benign lesions almost never harbor this mutation, and it is a specific mark of papillary thyroid carcinomas (PTCs), since its occurrence in the follicular histotype (FTCs) is basically missing.11-18 The frequency of this mutation in different types of thyroid tumors is represented in Figure 2. The high specificity of this mutation for the papillary malignant phenotype suggested its clinical application as marker for the detection of PTCs in patients with indeterminate fine needle aspiration biopsies. Indeed, several studies have demonstrated that application of BRAF mutation analysis to cytological samples improves the accuracy of presurgical diagnosis. [19][20][21][22] The high incidence of the BRAF V600E mutation and its association with the malignant phenotype of thyroid nodules has primed researchers to investigate a possible connection between this mutation and aggressive features of papillary cancers. In the past decade, the occurrence of the BRAF V600E mutation has been associated with several morphological and clinical features of PTCs (including extrathyroidal extension, lymph node and distant metastases, higher TNM stage and recurrence), fostering the suggestion that this mutation could be considered a marker of aggressiveness and should be employed in a clinical setting to define high risk profile PTC patients. However, in spite of this large scientific effort, the BRAF V600E mutation still does not take off as clinical prognostic marker. This may be consequence of the fact that the available association studies are conflicting, contradictory and far from being exhaustive. Conflicts between different studies can stem from a variety of issues including different patients' selection, different histological types included in the analysis, epi...

Cadherin-6 promotes EMT and cancer metastasis by restraining autophagy

“…To the best of our knowledge this represents one of the largest cohort of welldifferentiated PTCs with distant metastasis ever characterized at the molecular level. 35 As control, we selected 42 PTCs that did not develop distant metastasis based on a minimum follow-up of 7 years (Supplementary Table 1). Noticeably, we observed a striking correlation between CDH6 expression and the presence of distant metastasis (43.2% of DM-PTCs; 16.7% of control PTCs; P = 0.001; Table 1).…”

DIAGNOSIS OF ENDOCRINE DISEASE: High-yield thyroid fine-needle aspiration cytology: an update focused on ancillary techniques improving its accuracy

“…If found positive in a case diagnosed as suspicious for PC on cytology, a frozen section analysis (usually required in such a case) can be avoided and the patient can be directly referred to the surgeon to perform a total thyroidectomy as well as a selective lymph-node resection in some cases. Moreover, BRAF mutation PPV also warrants its use in the malignant category, even if its effective value as a prognostic marker is still under debate (18). The BRAF point mutations occur in up to 75% of PC cases, but can be lower due to important geographic variability.…”

“…Interestingly, this approach recently proved to be more cost-effective than molecular AFIRMA test (66). Finally, 18 F-FDG, a positron-emitting tracer widely used to study thyroid tumors, has been evaluated to address cytologically inconclusive thyroid nodules (Fig. 3C) Tc-MIBI and 18 F-FDG can help rule out malignancy and reduce unnecessary surgeries.…”

Contemporary and potential future molecular diagnosis of melanoma

“…Resistance to BRAF inhibitor therapy could rely on different mechanisms ( Figure 1), but it is most likely due to genetic heterogeneity of melanoma lesions. Indeed, BRAF V600E mutations are often found as oligoclonal event in solid tumors [17][18] and the BRAF inhibitors were found to mediate the homo-and heterodimerization of wild-type BRAF isoforms, increasing its signaling function and the activation of the downstream MAPK pathway (the so-called BRAF inhibitor paradox) [16,19] . The insurgence of resistance and the reactivation of MAPK pathway often leads to development of secondary tumors, including squamous cell carcinomas [20], new primary melanomas [21] or leukemia [22].…”