The Primary Occurrence of<i>BRAF<sup>V600E</sup></i>Is a Rare Clonal Event in Papillary Thyroid Carcinoma

Guerra, Anna; Sapio, Maria Rosaria; Marotta, Vincenzo; Campanile, Elisabetta; Rossi, Stefania; Forno, Irene; Fugazzola, Laura; Budillon, Alfredo; Moccia, Tania; Fenzi, Gianfranco; Vitale, Mario

doi:10.1210/jc.2011-0618

Cited by 140 publications

(128 citation statements)

References 37 publications

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“…In our training set, 82.3% of the population conventionally showed the BRAF mutation, which is consistent with previous Korean studies (Chung et al 2006, Kim et al 2009, Jung et al 2010. The BRAF positivity rate appears to be higher in our study than in other studies performing a quantitative analysis of BRAF mutations (Guerra et al 2012a,b, Gandolfi et al 2013. 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.…”

Section: Discussionsupporting

confidence: 91%

“…The presence of the BRAF mutation in tissues was considered important in the analysis. 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).…”

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: 91%

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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“…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. Additional alterations might be necessary to sustain transformation in BRAF V600E-positive tumors.…”

Section: Discussioncontrasting

confidence: 65%

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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“…Mutual exclusivity in PTCs of the most common genetic mutations, including BRAF and RAS mutations and RET/PTC rearrangements, indicate that each event is self-sufficient to constitutively activate the tumor-initiating MAPK pathway [6]. Conversely, more recently, a study that used pyrosequencing to determine the percentage of mutant BRAF alleles in conventional PTCs concluded that BRAF V600E is a rare clonal event and more often a nonclonal mutation, occurring late during PTC progression [7]. If confirmed, this finding would have important ramifications because it would undermine the rationale for using therapies targeted against this oncoprotein.…”

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confidence: 99%

BRAF mutation assessment in papillary thyroid cancer: are we ready to use it in clinical practice?

Puxeddu

2013

Endocrine

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The Primary Occurrence ofBRAF^V600EIs a Rare Clonal Event in Papillary Thyroid Carcinoma

Cited by 140 publications

References 37 publications

Quantification of BRAF V600E alleles predicts papillary thyroid cancer progression

Quantification of BRAF V600E alleles predicts papillary thyroid cancer progression

RAC1b overexpression in papillary thyroid carcinoma: a role to unravel

BRAF mutation assessment in papillary thyroid cancer: are we ready to use it in clinical practice?

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The Primary Occurrence ofBRAFV600EIs a Rare Clonal Event in Papillary Thyroid Carcinoma

Cited by 140 publications

References 37 publications

Quantification of BRAF V600E alleles predicts papillary thyroid cancer progression

Quantification of BRAF V600E alleles predicts papillary thyroid cancer progression

RAC1b overexpression in papillary thyroid carcinoma: a role to unravel

BRAF mutation assessment in papillary thyroid cancer: are we ready to use it in clinical practice?

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The Primary Occurrence ofBRAF^V600EIs a Rare Clonal Event in Papillary Thyroid Carcinoma