Perspective in pathologyB-RAF mutations in the etiopathogenesis, diagnosis, and prognosis of thyroid carcinomas☆
Introduction
Taking into consideration that 50% of the cases of human colon carcinoma present K-RAS mutations [1], Hanahan and Weinberg [2] speculated that the “remaining colonic tumors carry defects in other components of the growth signaling pathways that phenocopy RAS oncogene activation.”
In 2002, the Cancer Genome Project reported a high frequency in human malignancies of somatic activating mutations in a gene of the RAS-RAF-MEK-ERK pathway other than RAS—B-RAF [3]. Raf proteins are key members of the signaling pathway that are transducers of extracellular signals, through Ras small-GTPases, into the nucleus, in the signaling initiated by membrane receptor tyrosine kinases (RTK). Upon ligand binding (growth factors), RTKs are activated, therefore promoting the activation of guanine exchange factors such as Son of Sevenless. Activated guanine exchange factors promote the exchange of RAS-bound guanosine diphosphate by guanosine triphosphate, thus leading to a RAS active conformation. In fact, oncogenic RAS gene mutations stabilize RAS into a guanosine triphosphate–bound, hence constitutively active, form [4]. Active RAS, on its turn, recruits RAF to the membrane where it is activated (for a review, see Ref. [5]). Once activated, Raf proteins trigger the phosphorylation cascade of the “mitogen-activated protein kinase” pathway RAF-MEK-ERK. Of the several RAF isoforms, B-RAF appears to be the strongest activator of RAF-MEK-ERK pathway [6].
The study by Davies et al [3] and subsequent studies ascertained that B-RAF is mutated in a wide range of cancers, namely, in melanoma (63%-66%) [3], [7] and, in smaller frequencies, invasive micropapillary serous ovarian carcinoma (33%-40%) [3], [8] and colorectal carcinoma (11%-20%) [3], [9], [10]. In all these studies, B-RAF and RAS gene mutations were found to be mostly noncoexistent in the same tumor, being advanced; either way, each one would lead to the activation of the RAS-RAF-MEK-ERK pathway, thus confirming the hypothesis of Hanahan and Weinberg [2].
Almost all B-RAF mutations are clustered in 2 regions within the kinase domain: the glycine-rich loop that anchors adenosine triphosphate phosphates and is encoded by exon 11 and the activation loop, a phosphoregulatory region in which phosphorylations are required for full activity that is encoded by exon 15 [3]. The great majority of the mutations target the activation segment (>80%), and within it, a single mutation accounts for more than 90% of the cases [6]: a thymine for adenine transition at the nucleotide 1799 that leads to the substitution of a valine for a glutamic acid at the residue 600—B-RAFV600E (previously named as nucleotide 1796 and residue 599 [11]).
Section snippets
B-RAF mutations in thyroid tumors
RAS mutations have been known for a long time to occur frequently in lesions of the follicular cell lineage, namely, in follicular adenoma (FTA) (14%-33%) [12], [13], [14], [15], [16] and follicular carcinoma (FTC) (21%-50%) [13], [15], [16], and less frequently, in papillary thyroid carcinoma (PTC) (0%-21%) [12], [13], [15], [17].
Several screening studies performed in thyroid tumors consistently described high B-RAF mutation prevalences in PTC, ranging from 29% to 83% [18], [19], [20], [21],
B-RAF mutations in the etiopathogenesis of PTC
Known PTC genetic alterations other than B-RAF mutations are rearrangements of RET (RET/PTC) and NTRK1 genes and RAS gene point mutations. In some studies, these genetic events were screened together with B-RAF mutations, with prevalences of 8% to 33% for RET/PTC [18], [20], [43], [44], [45], 15% to 5% for NTRK1 rearrangements [44], [45], and 0% to 21% for RAS genes mutations [18], [20], [21], [44], [45]. These genetic events, B-RAF mutations included, are almost always noncoexistent in the
Genotype-phenotype associations in PTC
There seems to exist a trend toward an association between PTC histotypes and particular genetic alterations. The RET/PTC1 rearrangement is commonly associated with the conventional histotype [56], [57], [58], whereas RET/PTC3 rearrangement is correlated with the solid variant, particularly in the post-Chernobyl setting [59], [60], [61], [62], as well as with the tall cell variant [63]. By their turn, the activating mutations of RAS (mainly targeting codon 61 of N- and H-RAS) are particularly
Diagnostic value of B-RAF mutations
Given the specificity, within thyroid neoplasias, of B-RAF mutations to PTC, it is tempting to use their screening in the diagnosis of PTC. Molecular biology techniques were applied for the screening of B-RAF mutations, as well as of RET/PTC, in fine needle aspirates. The results obtained in these studies support the conclusion that the search for genetic alterations may be valuable in fine needle aspirates of thyroid lesions [65], [66], [69], [70], [71], [72]. Yet, the close relationship
Prognostic value of B-RAF mutations
Several clinicopathologic studies, as well as functional studies using thyroid-targeted B-RAFV600E transgenic mice [55] and B-RAFV600E-transfected thyroid cell lines [47], point to a higher aggressiveness of the B-RAF–mutated PTC cases. Some groups reported an association between B-RAF mutations and poor prognostic indicators, namely, the older age [23], [24], increased male incidence [21], extrathyroid extension [23], [75], regional metastases [25], [75], distant metastases [22], higher tumor
Therapeutic perspectives
The standard treatment of PTCs is well established and has provided excellent results in most cases. There are, nevertheless, several PTCs that carry a guarded prognosis and raise difficult therapeutic problems. It is conceivable that the information on B-RAF status may be important in the future to treat patients with primary, or most likely, recurrent PTCs responding badly to radioactive iodine. The same holds true for treating patients with B-RAF–mutated, poorly differentiated and
Acknowledgments
The authors thanks the colleagues of the Thyroid Group for their support and collaboration. Some of the work herein cited was supported by the Portuguese Science and Technology Foundation (FCT), both by a PhD grant to Vítor Trovisco (SFRH/BD/13055/2003) and by a project funding (POCTI project POCI/SAU-0BS/56175/2004).
We would like to apologize to the authors whose works were not cited because of space constraints or unintended omission.
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2020, Critical Reviews in Oncology/HematologyEffect of BRAF V600E mutation detection of fine-needle aspiration biopsy on diagnosis and treatment guidance of papillary thyroid carcinoma
2020, Pathology Research and PracticeInvestigation of BRAF V600E detection approaches in papillary thyroid carcinoma
2018, Pathology Research and PracticeCitation Excerpt :Importantly, many genetic alterations have been involved in PTCs, mostly engaging in the aberrant activation of the RAS–RAF–MEK–MAP kinase pathway. Specifically, the BRAF V600E mutation, reported in 18% to 87% [5,6], is the most common genetic change in PTC. As one of the vast majority BRAF mutations, the BRAF V600E mutation does not occur in follicular or medullary thyroid caricinomas or benign thyroid tumors.
BRAF genetic heterogeneity in papillary thyroid carcinoma and its metastasis
2014, Human PathologyCitation Excerpt :The BRAF V600E mutation (BRAF mutation) has been reported in 18% to 87% of thyroid cancers [1,2] including in up to 69% of papillary thyroid carcinomas (PTC) and in 20% to 40% anaplastic thyroid carcinomas (ATC) [3,4].
Applications and limitations of oncogene mutation testing in clinical cytopathology
2013, Seminars in Diagnostic Pathology
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This study was funded by the Portuguese Foundation for Science and Technology (Fundação para a Ciência e Tecnologia), Lisboa, Portugal, POCTI project POCI/SAU-0BS/56175/2004.