Allele Percentage of theBRAFV600E Mutation in Papillary Thyroid Carcinomas and Corresponding Lymph Node Metastases: No Evidence for a Role in Tumor Progression

Abstract

Context:The relevance of the BRAF V600E mutation in papillary thyroid carcinoma (PTC) as a negative prognostic factor is a subject of intense debate. This mutation has been associated with several clinicopathological features, but the lack of consistency among data does not support its usefulness as marker of tumor aggressiveness and poorer outcome. Due to the genetic heterogeneity of the tumor, both the occurrence and the allele percentage of the BRAF mutation should be considered to unravel this controversy.Objective: We aimed to evaluate the impact of the BRAF V600E mutation occurrence and the allele percentage on the metastatic process in PTCs. Study Design:The presence and allele percentage of the BRAF mutation were determined by pyrosequencing in 132 cases of well-differentiated PTCs with (n ϭ 37) or without lymph node metastases (LNMs) (n ϭ 95) and in 40 LNMs matched with 35 PTCs.Results: No significant differences were observed in either the occurrence or the allele percentage of V600E mutation between the 2 groups of PTCs with or without LNMs. The LNMs were heterogeneous for the V600E mutation as the primary lesions. Conclusions:In this study, the occurrence and percentage of the BRAF V600E mutated allele was not preferentially associated with the development of metastases and the average mutated allele percentage decreased as the tumor progresses from the primary site to the lymph node metastatic sites. These observations support the need to reevaluate the role of the BRAF V600E mutation as a negative prognostic marker in PTCs. (J Clin Endocrinol Metab 98: E934 -E942, 2013) P apillary thyroid carcinoma (PTC) accounts for approximately 90% of all thyroid cancers. Although most these tumors show an indolent behavior and favorable prognosis, a small but significant percentage behaves aggressively and results in poor clinical outcome (1). The identification of prognostic markers able to discriminate PTCs with more aggressive behavior from those with an indolent course would be of great relevance when planning therapeutic strategies. In this regard, the relevance of BRAF (v-Raf murine sarcoma viral oncogene homolog B1) mutations as marker of tumor aggressiveness and poorer outcome in thyroid cancer has been recently a subject of intense debate.The BRAF V600E mutation, resulting from the BRAFT1799A transversion, is the most common genetic mutation in PTC, with a mean frequency of 45% of mu- Abbreviations: BRAF, v-Raf murine sarcoma viral oncogene homolog B1; IHC, immunohistochemistry; LN, lymph node; LNM, lymph node metastasis; PTC, papillary thyroid carcinoma.

TERT promoter mutations are associated with distant metastases in papillary thyroid carcinoma

“…BRAF V600E mutation was present in 54 of the 121 PTC samples analyzed (frequency: 0.44). As previously described, no association between the occurrence of this mutation and the presence of distant metastases was detected (31,32). An association between the presence of TERT C228T and BRAF V600E was observed in the DM-PTCs group (46% of TERT C228T-mutated in BRAFpositive cases vs 14% in BRAF-negative cases; PZ0.03).…”

“…Part of these samples corresponded to the cases described in previous studies (31,32). All the patients underwent total thyroidectomy and in 80% of the cases they underwent also ipsilateral central neck dissection.…”

Quantification of BRAF V600E alleles predicts papillary thyroid cancer progression

“…However, the subclonality of the BRAF mutation in PTCs has recently been suggested (Guerra et al 2012a). In this context, the quantification of the mutated allele was emphasised in terms of predicting prognosis (Guerra et al 2012b); however, several studies have shown results contradictory to those findings, as determined by the quantification of mutated alleles (Gandolfi et al 2013) and immunohistochemical (IHC) staining (Ghossein et al 2013). The proper value of the quantification of the mutated allele remains in debate and requires further evaluation.…”

Application of molecular biology of differentiated thyroid cancer for clinical prognostication

“…This represents a crucial issue with possible dramatic impact not only on the biological perspective but also on clinical implications related to the mutation, with the inclusion of the prognostic role. Particularly, 2 studies (Guerra et al 2012b, Gandolfi et al 2013) opened a burning issue among researchers dealing with thyroid carcinogenesis. In both papers, authors searched for BRAF V600E in PTC samples by means of pyrosequencing, a sequencing-by-synthesis method providing the exact percentage of alleles (and therefore cells) bearing the mutation (Ronaghi et al 1998).…”