BRAF(V600E) mutation and the biology of papillary thyroid cancer

Frasca, Francesco; Nucera, Carmelo; Pellegriti, Gabriella; Gangemi, Pietro; Attard, Marco; Stella, M.; Loda, Massimo; Vella, Veronica; Giordano, Carla; Trimarchi, Francesco; Mazzon, Emanuela; Belfiore, Antonino; Vigneri, Riccardo

doi:10.1677/erc-07-0212

Cited by 212 publications

(199 citation statements)

References 82 publications

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“…However, Frasca et al. 20 reported there was no statistical difference in BRAF V600E prevalence in Italian PTCs from an iodine‐sufficient area (39.6%) or iodine‐deficient area (34%) ( P = 0.44). Although there are some differences in intrinsic and extrinsic factors, other than iodine intake, between Japanese and Vietnamese residents, our findings support a hypothesis that the amount of iodine consumption is not associated with the frequency of BRAF V600E in PTCs.…”

Section: Discussionmentioning

confidence: 86%

“…27 reported that the prevalence of the BRAF V600E mutation in PTCs was significantly higher in iodine‐rich areas than in iodine‐normal areas in China. Another study from Italy, however, did not find a statistical difference in the BRAF V600E mutation rate of PTCs between iodine‐rich and iodine‐deficient areas 20. The prevalence of RAS codon 61 mutations in FTCs was reported to be five times higher in the iodine‐deficient country of Hungary than in iodine‐rich Canada 28, and a possible relationship of iodine deficiency and generation of RET/PTC rearrangements has been suggested 29.…”

Section: Introductionmentioning

confidence: 95%

“…BRAF mutations are the most common mutation in PTCs, and the transverse point mutation at codon 600 ( BRAF V600E) is the most common type of BRAF mutations 15, 16, 17. Several studies demonstrated a strong association between BRAF mutations and poor clinicopathological outcomes for patients with PTCs 18, 19, 20. RAS mutations can be found in follicular neoplasms and are more common in FTCs (40–50%) than in follicular thyroid adenomas (20–40%) 21, 22, 23, 24.…”

Section: Introductionmentioning

confidence: 99%

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Genetic alterations of differentiated thyroid carcinoma in iodine‐rich and iodine‐deficient countries

et al. 2016

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BRAF V600E mutation, RET rearrangements, and RAS mutations are the common genetic alterations in differentiated thyroid carcinomas derived from follicular thyroid cells. However, the relationship between these alterations and iodine intake is still controversial. To clarify the influence of iodine intake on the occurrence of differentiated thyroid carcinomas, we performed molecular analyses for two differentiated carcinomas, papillary thyroid carcinomas (PTCs) and follicular thyroid carcinomas (FTCs), from an iodine‐rich country (Japan) and an iodine‐deficient country (Vietnam). We examined 120 PTCs (67 Japanese and 53 Vietnamese) and 74 FTCs (51 Japanese and 23 Vietnamese). We carried out allele‐specific polymerase chain reaction (AS‐PCR) for BRAF V600E, PCR and direct sequencing for RAS mutations (codon 12, 13, and 61 in NRAS,HRAS, and KRAS), and RT‐PCR for RET/PTC1 and RET/PTC3. BRAF V600E was present in 55/67 (82.1%) Japanese PTCs and 44/53 (83%) Vietnamese PTCs. RET/PTC1 was identified in only one PTC from each country, and no samples had RET/PTC3. NRAS mutation was found in 17/51 (33.3%) Japanese FTCs and 4/23 (17.4%) Vietnamese FTCs. NRAS mutation was cited in codon 61 (20 cases) and codon 12 (one case). None of FTCs had KRAS or HRAS mutations. There were no significant differences in the prevalence of BRAF V600E,RET/PTC, or RAS mutations between the two countries. Our study showed no differences in genetic alterations of thyroid cancers from iodine‐rich and iodine‐deficient countries, possibly suggesting that iodine intake might not affect the genetic alterations of differentiated thyroid cancer.

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Section: Discussionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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Genetic alterations of differentiated thyroid carcinoma in iodine‐rich and iodine‐deficient countries

et al. 2016

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“…BRAF mutations are associated with poor clinical prognosis due to extrathyroid invasion and higher risk of relapse and metastasis. 19 Mutations in the family of RAS oncogenes, which encode for G-proteins that also convey signals to the MAPK pathway, are more common in follicular carcinomas (FTC) 20 and in follicular variant of papillary carcinoma (fvPTC). 21 Point mutations in the HRAS, KRAS, and NRAS genes are associated with specific domains of the protein and are able either to increase its affinity for substrate (substitution in residues 12 and 13) or to inactivate the autocatalytic GTPase function (residue 61).…”

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confidence: 99%

A High-Resolution Melting Protocol for Rapid and Accurate Differential Diagnosis of Thyroid Nodules

Mancini

Pinzani

Pupilli

et al. 2012

The Journal of Molecular Diagnostics

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Thyroid cancer is the most common malignancy of the endocrine system, accounting for approximately 1% of all malignancies in Western countries. 1 The incidence of thyroid cancer has increased 2.6-fold in the last 30 years. This change is attributed not only to an increment in papillary thyroid carcinoma, 2 but also to more wisely conducted medical surveillance and improvements in diagnostic tools. 3 The large majority of thyroid nodules, as discovered with the use of new diagnostic imaging techniques, are asymptomatic and benign. In this context, diagnostic studies are becoming essential to identify the small fraction of thyroid nodules that harbor malignant disease and to predict when surgery is indicated. Fine-needle aspiration biopsy (FNAB) has emerged over the past 30 years as an accurate and cost-effective procedure for the preoperative screening of thyroid nodules, representing the gold standard for differential diagnosis of benign and malignant nodules. 4 Under recent guidelines, 5,6 cytological smears are classified in five categories for the diagnostic report: Thy 1, nondiagnostic; Thy 2, benign or negative for malignant cells; Thy 3, all follicular lesions (including atypia/ follicular lesion of undetermined significance and follicular neoplasm or suspicious for follicular neoplasm); Thy 4, suspicious; and Thy 5, diagnostic for malignancy.Although the overall accuracy of FNAB is considered excellent, approximately 30% of cytological aspirates do not allow definitive diagnosis of malignancy, because of intrinsic and unavoidable characteristics of samples. 7 The major limitations of FNAB procedures are linked to inadequate and indeterminate specimens and, in that sense, are also linked respectively to the nondiagnostic or follicular lesions categories. 8,9 Thus, a clinical need emerges for the characterization of aspirates with suspicious features but with unsatisfactory cellularity, to allow accurate distinction of benign from malignant forms of follicular lesions.Several somatic mutations have been identified in thyroid cancer, stimulating the search for genetic alterations in FNAB that could increase the diagnostic accuracy of traditional cytology. Numerous studies have demonstrated that identification of specific mutations in cytological specimens can assist in the diagnosis by FNAB and in the clinical decision to excise the nodule and to intensify the follow-up. 10 -16 In most cases, genetic alterations are represented by activating mutations of oncogenes that are mutually exclusive and linked to distinct histological subtypes, with a demonstrated pathogenic role in thyroid cell transformation as effectors of the RAS/RAF/ MAPK signaling cascade.The presence of BRAF mutations, a frequent alteration in papillary carcinoma (PTC), evolves into an unregulated activation of the intracellular MAPK pathway that can promote tumorigenesis and tumor progression. The main mutation of BRAF, identified exclusively in PTC, affects

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“…From the clinicopathological perspective, BRAF V600E was associated with the aggressive tall cell variant of PTC. Although still controversial, the majority of studies also reported the association of mutated BRAF with several other clinicopathological features having negative prognostic impact, such as lymph node metastases, extrathyroidal extension and advanced disease stage (Xing et al 2005, Kebebew et al 2007, Lee et al 2007, Frasca et al 2008, Wang et al 2008. Owing to this body of evidence, BRAF V600E has been considered the best candidate as molecular prognosticator of PTC, and several prognostic studies have been dedicated to assess its relationship with clinical outcome.…”

Section: Braf V600ementioning

confidence: 99%

Application of molecular biology of differentiated thyroid cancer for clinical prognostication

Marotta¹,

Sciammarella²,

Colao³

et al. 2016

Endocrine-Related Cancer

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Although cancer outcome results from the interplay between genetics and environment, researchers are making a great effort for applying molecular biology in the prognostication of differentiated thyroid cancer (DTC). Nevertheless, role of molecular characterisation in the prognostic setting of DTC is still nebulous. Among the most common and well-characterised genetic alterations related to DTC, including mutations of BRAF and RAS and RET rearrangements, BRAF V600E is the only mutation showing unequivocal association with clinical outcome. Unfortunately, its accuracy is strongly limited by low specificity. Recently, the introduction of next-generation sequencing techniques led to the identification of TERT promoter and TP53 mutations in DTC. These genetic abnormalities may identify a small subgroup of tumours with highly aggressive behaviour, thus improving specificity of molecular prognostication. Although knowledge of prognostic significance of TP53 mutations is still anecdotal, mutations of the TERT promoter have showed clear association with clinical outcome. Nevertheless, this genetic marker needs to be analysed according to a multigenetic model, as its prognostic effect becomes negligible when present in isolation. Given that any genetic alteration has demonstrated, taken alone, enough specificity, the co-occurrence of driving mutations is emerging as an independent genetic signature of aggressiveness, with possible future application in clinical practice. DTC prognostication may be empowered in the near future by non-tissue molecular prognosticators, including circulating BRAF V600E and miRNAs. Although promising, use of these markers needs to be refined by the technical sight, and the actual prognostic value is still yet to be validated. 23:11Review V Marotta et al. Molecular prognosis in thyroid cancer

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BRAF(V600E) mutation and the biology of papillary thyroid cancer

Cited by 212 publications

References 82 publications

Genetic alterations of differentiated thyroid carcinoma in iodine‐rich and iodine‐deficient countries

Genetic alterations of differentiated thyroid carcinoma in iodine‐rich and iodine‐deficient countries

A High-Resolution Melting Protocol for Rapid and Accurate Differential Diagnosis of Thyroid Nodules

Application of molecular biology of differentiated thyroid cancer for clinical prognostication

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