Is the BRAFV600E mutation useful as a predictor of preoperative risk in papillary thyroid cancer?

Nam, Jong-Ho; Jung, Chan Kwon; Song, Byung Joo; Lim, Dong Jun; Chae, Byung Joo; Lee, Nam Seop; Park, Woo Chan; Kim, Jeong Soo; Jung, Sang Seol; Bae, Ja Seong

doi:10.1016/j.amjsurg.2011.02.013

Cited by 72 publications

(77 citation statements)

References 24 publications

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“…As the incidence of BRAF mutation in PTCs varies Using a conventional approach, there was no significant association of BRAF positivity with clinical/ pathological parameters other than the presence of extrathyroidal extension and the absence of thyroiditis. The association of BRAF mutation with the presence of extrathyroidal extension and the absence of thyroiditis , Nam et al 2012) and the absence of thyroiditis (Sargent et al 2006, Kim et al 2009) was concordant with previous studies. By contrast, taking a quantitative approach to describe the BRAF-positive population revealed that groups with a high percentage of allelic mutation were closely related to poor prognostic parameters (such as tumour size, extrathyroidal extension, lymph node metastasis and the number of metastatic lymph nodes) compared with low mutation-percentage groups.…”

Section: Discussionsupporting

confidence: 79%

“…Considering the availability of current targeted therapies that include a BRAF inhibitor, the identification of the BRAF mutation may also be a good candidate marker for the prediction of response to targeted therapies. Nevertheless, there remains controversy surrounding the prognostic role of the BRAF mutation, as multiple studies have failed to illustrate a prognostic role for the BRAF mutation (Kim et al 2005, Cheng et al 2011, Eloy et al 2011, Nam et al 2012, Paulson et al 2012, Sassolas et al 2012.…”

Section: Introductionmentioning

confidence: 99%

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Quantification of BRAF V600E alleles predicts papillary thyroid cancer progression

Kim¹,

Bae²,

Lim³

et al. 2014

Endocrine-Related Cancer

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The BRAF V600E mutation is the most common genetic alteration in thyroid cancer. However, its clinicopathological significance and clonal mutation frequency remain unclear. To clarify the inconsistent results, we investigated the association between the allelic frequency of BRAF V600E and the clinicopathological features of classic papillary thyroid carcinoma (PTC). Tumour tissues from two independent sets of patients with classic PTC were manually microdissected and analysed for the presence or absence of the BRAF mutation and the mutant allelic frequency using quantitative pyrosequencing. For external validation, the Cancer Genome Atlas (TCGA) data were analysed. The BRAF V600E mutation was found in 264 (82.2%) out of 321 classic PTCs in the training set. The presence of BRAF V600E was only associated with extrathyroidal extension and the absence of thyroiditis. In BRAF V600E-positive tumours, the mutant allelic frequency varied from 8 to 41% of the total BRAF alleles (median, 20%) and directly correlated with tumour size and the number of metastatic lymph nodes. Lymph node metastases were more frequent in PTCs with a high (R20%) abundance of mutant alleles than in those with a low abundance of mutant alleles (PZ0.010). These results were reinforced by validation dataset (nZ348) analysis but were not reproduced in the TCGA dataset. In a population with prevalent BRAF mutations, quantitative analysis of the BRAF mutation could provide additional information regarding tumour behaviour, which is not reflected by qualitative analysis. Nonetheless, prospective studies are needed before the mutated allele percentage can be considered as a prognostic factor.

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Section: Discussionsupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Quantification of BRAF V600E alleles predicts papillary thyroid cancer progression

Kim¹,

Bae²,

Lim³

et al. 2014

Endocrine-Related Cancer

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“…The most prevalent subgroup of classical and follicular variants of PTC showed no association of BRAF mutation with poor prognostic factors or poor outcome. Our findings corroborated recent studies (20,21,22,23) and also discarded the association of p.V600E with higher frequency of cervical LN and distant metastases (13,24,25,26). In order to justify the lack of association, it has also been proposed that it is not the intratumoral presence of BRAF mutation that determines prognosis but the higher frequency of mutant BRAF alleles, identified in an innovatory analysis of pyrosequencing technique, that favors more frequent recurrence (27).…”

Section: Clinical Study D L S Danilovic and Others Preoperative Molecsupporting

confidence: 80%

Pre-operative role of BRAF in the guidance of the surgical approach and prognosis of differentiated thyroid carcinoma

Danilovic

Lima

Domingues

et al. 2014

European Journal of Endocrinology

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Objective: The p.V600E BRAF and RAS mutations are found in 30-80% of differentiated thyroid carcinoma (DTC). BRAF mutation has been associated with poor prognosis. This study investigated the role of molecular studies in preoperative diagnosis of DTC and the association of p.V600E mutation with prognostic factors. Design: Prospective study. Methods: A total of 202 patients with cytological diagnosis of Bethesda III-VI underwent preoperative molecular studies and subsequent thyroidectomy. p.V600E and RAS mutations were studied in the cytology smears, using real-time PCR genotyping technique. The BRAF mutation (BRAF C or BRAF K ) was correlated with histological and clinical findings. Results: Molecular study of 172 nodules with Bethesda III-V cytology improved negative predictive value and accuracy of Bethesda III and IV diagnosis. BRAF mutation was present in 65% of 94 DTC and p.Q61R NRAS in one. Except for age, BRAF C and BRAF K did not differ in sex, tumor size, histological subtype, multifocality, vascular invasion, extrathyroidal extension, or prognostic staging. Among papillary carcinomas, lymph node (LN) metastasis was diagnosed in 23% BRAF C and 37% BRAF K . Distant metastasis occurred in four BRAF K . Recurrent or persistent disease was more frequent in BRAF K (26.7 vs 3.3% BRAF C , PZ0.002) along follow-up of 29.8G10 months. BRAF C patients without LN metastasis by pre-operative evaluation submitted to thyroidectomy with central neck dissection (CND) had more frequent LN metastasis (45 vs 5% no CND, PZ0.002), but no difference in clinical outcome was observed. Conclusions: Pre-operative identification of BRAF mutation improved cytological diagnosis of DTC, but it was not associated with poor prognostic factors. Prophylactic CND did not guarantee better outcome in BRAF C patients.

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“…The prognostic value of the BRAF V600E mutation in PTC patients has been an object of extensive studies. While many studies report an association of BRAF V600E mutation with a more aggressive behavior (13,16,17,20,22), others, including the present series, failed to document such association (14,18,19,21). These apparently conflicting results have to be reevaluated in light of a recent study (38) demonstrating that clonal occurrence of BRAF mutation is a rare event in PTC and that more frequently this mutation affects only a subpopulation of cells.…”

Section: Discussioncontrasting

confidence: 44%

“…The V600E mutation constitutively activates BRAF kinase, leading to prolonged stimulation of the MAPK pathway, which ultimately leads to uncontrolled cell proliferation and faulty apoptosis (8,9,12). The majority of studies have associated BRAF V600E mutation with a more aggressive PTC behavior, whereas a few studies failed to reproduce this finding (13,14,15,16,17,18,19,20,21,22). Still, its value as a prognostic marker remains incompletely established and other players might be implicated, justifying the search for additional molecular markers.…”

Section: Introductionmentioning

confidence: 91%

RAC1b overexpression in papillary thyroid carcinoma: a role to unravel

Silva¹,

Carmo²,

Bugalho

2013

European Journal of Endocrinology

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Context: The BRAF V600E mutation is the most frequent genetic alteration in papillary thyroid carcinoma (PTC). In colorectal cancer, BRAF V600E was described to functionally cooperate with RAC1b, a hyperactive splice variant of the small GTPase RAC1, to sustain cell survival. This interplay has never been investigated in PTCs.Objective: We aimed to analyze the expression of RAC1b in PTC and correlate its expression with BRAF V600E mutational status, histopathological features, and clinical outcome. Patients and methods: Sixty-one patients and 87 samples (61 PTCs and 26 normal thyroid tissues) were included. Patients were divided into two groups based on longitudinal evolution and final outcome. RAC1b expression levels were determined by quantitative RT-PCR and western blotting. Results: RAC1b was expressed in thyroid and overexpressed in 46% of PTCs. Neither RAC1b overexpression nor V600E mutation correlated with histopathological features classically associated with worse prognosis. RAC1b overexpression was significantly associated with both V600E mutation (PZ0.0008) and poor clinical outcome (PZ0.0029). Whereas BRAF V600E alone did not associate with patient outcome (PZ0.2865), the association of RAC1b overexpression with BRAF V600E was overrepresented in the group with poorer clinical outcome (PZ0.0044). Conclusions: Present results document, for the first time, expression of RAC1b in normal thyroid cells as well as overexpression in a subset of PTCs. Furthermore, they suggest a possible interplay between BRAF V600E and RAC1b contributing to poor clinical outcome. Future studies are needed to clarify the oncogenic potential of RAC1b in thyroid carcinogenesis.

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Is the BRAFV600E mutation useful as a predictor of preoperative risk in papillary thyroid cancer?

Cited by 72 publications

References 24 publications

Quantification of BRAF V600E alleles predicts papillary thyroid cancer progression

Quantification of BRAF V600E alleles predicts papillary thyroid cancer progression

Pre-operative role of BRAF in the guidance of the surgical approach and prognosis of differentiated thyroid carcinoma

RAC1b overexpression in papillary thyroid carcinoma: a role to unravel

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