Recent Developments in the Molecular Biology of the Thyroid

Nikiforov, Yuri E.

doi:10.1007/978-1-4419-1069-1_10

Cited by 5 publications

(4 citation statements)

References 215 publications

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“…21 Several studies 11,[22][23][24] have suggested that mutation in RAS genes comprise a negligible portion, if any, of pediatric PTCs. Given the common signaling pathway of these oncogenes, constitutive activation in any one member has been considered a mutually exclusive event.…”

Section: 20mentioning

confidence: 99%

Mutation in BRAF and Other Members of the MAPK Pathway in Papillary Thyroid Carcinoma in the Pediatric Population

Gertz

Nikiforov

Rehrauer

et al. 2016

Archives of Pathology &Amp; Laboratory Medicine

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Context.-Papillary thyroid carcinoma (PTC) is an uncommon tumor in the pediatric population. A limited number of studies have examined genetic mutations affecting the mitogen-activated protein kinase (MAPK) pathway in the pediatric population.Objective.-To examine mutations affecting this pathway in PTC in our pediatric population and compare the BRAF V600E mutation rates in pediatric and adult tumors.Design.-Eighty-four patients, including 14 pediatric and 70 adult, with PTC were tested for the BRAF V600E mutation by using real-time polymerase chain reaction and sequencing. Additionally, we examined the rate of RAS point mutations with real-time polymerase chain reaction and rearrangements of RET/PTC1 and RET/PTC3 in the pediatric group with fluorescence in situ hybridization. Clinical and histologic data were compared as well.Results.-Of 77 tumors that had an interpretable result, the BRAF V600E mutant was identified in 4 of 13 pediatric patients (31%) and 43 of 64 adult patients (67%), which was a significant difference (using Fisher exact test, P ¼ .03). One pediatric and 6 adult cases did not reveal an interpretable result with melting curve analysis. One of these cases harbored a rare 3-base pair deletion mutation (c.1799_1801delTGA). Mutations in RAS genes were not seen in any pediatric tumors. One tumor with a RET/PTC1 rearrangement and another with RET/PTC3 were identified in the pediatric population (15%).Conclusions.-The rate of the BRAF V600E mutation in the pediatric population is significantly lower than that seen in the adult population. Mutations in RAS do not contribute significantly to pediatric PTC. This experience from our institution adds to the growing body of knowledge regarding tumor genetics in pediatric PTC.(Arch Pathol Lab Med. 2016;140:134-139; doi: 10.5858/ arpa.2014-0612-OA) P apillary thyroid carcinoma (PTC) is an uncommon tumor in the pediatric population. Despite having an excellent prognosis with long-term mortality rates of less than 1%, 1,2 pediatric patients with PTC tend to present with advanced disease often with increased rates of extrathyroidal tumor extension, lymphovascular invasion, and distant metastases. 1,3-5The distinct clinical nature of papillary thyroid cancer in the pediatric population has prompted interest in the molecular tumorigenesis. The mitogen-activated protein kinase (MAPK) pathway includes components of particular interest, including BRAF, RAS, and RET. Between 37% and 52% of PTCs have been linked to the specific BRAF mutation V600E, and clinical correlations support that this foretells a more aggressive disease course in adults. [6][7][8][9] The incidence of this BRAF mutation in the pediatric population is thought to be lower than in adults with rates of 0% to 37%, 10-15 though 1 recent series 16 revealed a rate of 63%. The rearrangement mutations of RET are also considered a major contributor to PTC tumorigenesis, but rates of this mutation have fluctuated widely in reported series.17 RET/PTC rearrangements have been associated with young age 18 an...

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Section: 20mentioning

confidence: 99%

Mutation in BRAF and Other Members of the MAPK Pathway in Papillary Thyroid Carcinoma in the Pediatric Population

Gertz

Nikiforov

Rehrauer

et al. 2016

Archives of Pathology &Amp; Laboratory Medicine

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“…Indeed, some authors have suggested that RET rearrangements are associated with local invasion and distant metastases (17,26,62,63,64,65) while other authors associated with early-stage small PTCs and better prognosis (30,66,67,68,69,70). However, these studies assumed that all types of rearrangement have comparable properties and considered them as a group (19).…”

Section: Discussionmentioning

confidence: 99%

“…A wide range of prevalence of RET/PTC rearrangements in human PTC has been reported, ranging from 3% in Saudi Arabia, 29-35% in Italy, 40% in Canada, to 85% in Australia (15,16,17,18), which can be attributed to ethnical and geographic variability as well as to different sensitivities of detection methods, tumor heterogeneity, age, and radiation exposure (6,19,20,21,22,23,24,25,26,27,28,29,30,31). Indeed, non-clonal RET/PTC rearrangements have been found not only in PTC but also in 10-45% of follicular thyroid adenomas, oncocytic thyroid tumors, and Hashimoto's thyroiditis (30,32,33,34,35,36,37,38,39).…”

Section: Introductionmentioning

confidence: 99%

Break–apart interphase fluorescence in situ hybridization assay in papillary thyroid carcinoma: on the road to optimizing the cut-off level for RET/PTC rearrangements

Colato

Vicentini

Cantara

et al. 2015

European Journal of Endocrinology

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Objective: Chromosomal rearrangements of the RET proto-oncogene is one of the most common molecular events in papillary thyroid carcinoma (PTC). However, their pathogenic role and clinical significance are still debated. This study aimed to investigate the prevalence of RET/PTC rearrangement in a cohort of BRAF WT PTCs by fluorescence in situ hybridization (FISH) and to search a reliable cut-off level in order to distinguish clonal or non-clonal RET changes. Design: Forty BRAF WT PTCs were analyzed by FISH for RET rearrangements. As controls, six BRAFV600E mutated PTCs, 13 follicular adenomas (FA), and ten normal thyroid parenchyma were also analyzed. Methods: We performed FISH analysis on formalin-fixed, paraffin-embedded tissue using a commercially available RET break-apart probe. A cut-off level equivalent to 10.2% of aberrant cells was accepted as significant. To validate FISH results, we analyzed the study cohort by qRT-PCR. Results: Split RET signals above the cut-off level were observed in 25% (10/40) of PTCs, harboring a percentage of positive cells ranging from 12 to 50%, and in one spontaneous FA (1/13, 7.7%). Overall, the data obtained by FISH matched well with qRT-PCR results. Challenging findings were observed in five cases showing a frequency of rearrangement very close to the cut-off. Conclusions: FISH approach represents a powerful tool to estimate the ratio between broken and non-broken RET tumor cells. Establishing a precise FISH cut-off may be useful in the interpretation of the presence of RET rearrangement, primarily when this strategy is used for cytological evaluation or for targeted therapy.

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“…Jedan od načina aktivacije ovog puta su tačkaste mutacije koje zahvataju BRAF i RAS gene, a drugi je aktivacija RET ili TRK protoonkogena putem intrahromozomske inverzije ili translokacije (11).…”

Section: Uvodunclassified