Genotyping of an Italian papillary thyroid carcinoma cohort revealed high prevalence of BRAF mutations, absence of RAS mutations and allowed the detection of a new mutation of BRAF oncoprotein (BRAFV599Ins)

Carta, Claudio; Moretti, Sonia; Passeri, L.; Barbi, Flavia; Avenia, Nicola; Cavaliere, Antonio; Monacelli, Massimo; Macchiarulo, Antonio; Santeusanio, Fausto; Tartaglia, Marco; Puxeddu, Efisio

doi:10.1111/j.1365-2265.2005.02401.x

Cited by 76 publications

(45 citation statements)

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“…32 Activating mutations of all three RAS oncogenes (KRAS, HRAS and NRAS) have historically been associated with a higher frequency in follicular than in papillary tumours. 33,34 A recent study by Carta et al 35 found an absence of RAS mutations in an Italian papillary thyroid carcinoma cohort but the presence of RAS oncogenic mutations in 75% of follicular thyroid carcinomas.…”

Section: Expression Patternsmentioning

confidence: 97%

A molecular expression signature distinguishing follicular lesions in thyroid carcinoma using preamplification RT-PCR in archival samples

et al. 2007

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Follicular variant of papillary thyroid carcinoma is a lesion that frequently causes difficulties from a diagnostic perspective in the laboratory. The purpose of this study was to interrogate a cohort of archival thyroid lesions using gene expression analysis of a panel of markers proposed to have utility as adjunctive markers in the diagnosis of thyroid neoplasia and follicular variant of papillary thyroid carcinoma in particular. Laser Capture Microdissection was used to procure pure cell populations for extraction. In addition a novel, multiplex preamplification technique was used to facilitate analysis of multiple targets. The panel comprised: HLA-DMA, HLA-DBQ1, CD74, CSNK1G2, IRF3, KRAS2, LYN, MT1K, MT1X, RAB23, TGFB1 and TOP2A, with CDKN1B as an endogenous control. Expression profiles for each target were generated using TaqMan s Real-Time PCR. HLA-DMA, HLA-DQB1, MT1X, CSNK1G2 and RAB23 were found to be differentially expressed (Po0.05) when comparing follicular adenoma and follicular variant of papillary thyroid carcinoma. Comparison of follicular adenoma and follicular thyroid carcinoma groups showed significant differential expression for MT1K, MT1X and RAB23 (Po0.05). Comparison of the papillary thyroid carcinoma group (classic and follicular variants) and the follicular adenoma group showed differential expression for CSNK1G2, HLA-DQB1, MT1X and RAB23 (Po0.05). Finally, KRAS2 was found to be differentially expressed (Po0.05) when comparing the papillary thyroid carcinoma and follicular thyroid carcinoma groups. This panel of molecular targets discriminates between follicular adenoma, papillary thyroid carcinoma, follicular variant of papillary thyroid carcinoma and follicular thyroid carcinoma by their expression repertoires. It may have utility for broader use in the setting of fine-needle aspiration cytology and could improve the definitive diagnosis of certain categories of thyroid malignancy.

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Section: Expression Patternsmentioning

confidence: 97%

A molecular expression signature distinguishing follicular lesions in thyroid carcinoma using preamplification RT-PCR in archival samples

et al. 2007

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“…Approximately 95% of all BRAF mutations involve a T>A transversion at gene position 1799, resulting in valine to glutamate amino acid substitution at position 600 of the protein (V600E). Other described alterations in the BRAF gene include the A>G transversion at gene position 1801 (K601E), fusion with the A-kinase anchor protein 9 (AKAP9) gene and small in-frame insertions or deletions around codon 600 (24)(25)(26).…”

Section: Papillary Thyroid Carcinomamentioning

confidence: 99%

Signaling pathways in follicular cell-derived thyroid carcinomas

Romitti

Ceolin

Siqueira

et al. 2012

International Journal of Oncology

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Abstract. Thyroid carcinoma is the most common malignant endocrine neoplasia. Differentiated thyroid carcinomas (DTCs) represent more than 90% of all thyroid carcinomas and comprise the papillary and follicular thyroid carcinoma subtypes. Anaplastic thyroid carcinomas correspond to less than 1% of all thyroid tumors and can arise de novo or by dedifferentiation of a differentiated tumor. The etiology of DTCs is not fully understood. Several genetic events have been implicated in thyroid tumorigenesis. Point mutations in the BRAF or RAS genes or rearranged in transformation (RET)/papillary thyroid carcinoma (PTC) gene rearrangements are observed in approximately 70% of papillary cancer cases. Follicular carcinomas commonly harbor RAS mutations and paired box gene 8 (PAX8)-peroxisome proliferator-activated receptor γ (PPARγ) rearrangements. Anaplastic carcinomas may have a wide set of genetic alterations, that include gene effectors in the mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K) and/or β-catenin signaling pathways. These distinct genetic alterations constitutively activate the MAPK, PI3K and β-catenin signaling pathways, which have been implicated in thyroid cancer development and progression. In this context, the evaluation of specific genes, as well as the knowledge of their effects on thyroid carcinogenesis may provide important information on disease presentation, prognosis and therapy, through the development of specific tyrosine kinase targets. In this review, we aimed to present an updated and comprehensive review of the recent advances in the understanding of the genetic basis of follicular cell-derived thyroid carcinomas, as well as the molecular mechanisms involved in tumor development and progression.

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“…12,14 Other and rare mechanisms of BRAF activation in papillary thyroid cancer include K601E point mutation, small in-frame insertions or deletions surrounding codon 600, [15][16][17] and AKAP9-BRAF rearrangement, which is more common in papillary carcinomas associated with radiation exposure. 18 In addition to papillary carcinomas, BRAF is found mutated in thyroid anaplastic and poorly differentiated carcinomas, typically in those tumors that also contain areas of well-differentiated papillary carcinoma.…”

Section: Brafmentioning

confidence: 99%

Thyroid carcinoma: molecular pathways and therapeutic targets

2008

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Thyroid cancer is the most common malignant tumor of the endocrine system. The most frequent type of thyroid malignancy is papillary carcinoma. These tumors frequently have genetic alterations leading to the activation of the mitogen-activated protein kinase (MAPK) signaling pathway. Most common mutations in papillary carcinomas are point mutations of the BRAF and RAS genes and RET/PTC rearrangement. These genetic alterations are found in 470% of papillary carcinomas and they rarely overlap in the same tumor. Most frequent alterations in follicular carcinomas, the second most common type of thyroid malignancy, include RAS mutations and PAX8-PPARc rearrangement. RET point mutations are crucial for the development of medullary thyroid carcinomas. Many of these mutations, particularly those leading to the activation of the MAPK pathway, are being actively explored as therapeutic targets for thyroid cancer. A number of compounds have been studied and showed antitumor effects in preclinical studies and are being tested in ongoing clinical trials. Modern Pathology ( Keywords: thyroid cancer; mutations; MAPK; BRAF; RET; inhibitors Thyroid cancer is the most common malignant tumor of the endocrine system and accounts for approximately 1% of all newly diagnosed cancer cases.1 The most frequent type of thyroid malignancy is papillary carcinoma, which constitutes B80% of all cases. Papillary carcinomas frequently have genetic alterations leading to the activation of the mitogen-activated protein kinase (MAPK) signaling pathway (Figure 1). Those include RET/ PTC rearrangement and point mutations of the BRAF and RAS genes. Mutations involving one of these genes are found in 470% of papillary carcinomas and they rarely overlap in the same tumor 2-4 (Table 1). Frequent genetic alterations in follicular carcinomas, the second most common type of thyroid malignancy, include RAS mutations and PAX8-PPARg rearrangement. RET point mutations are crucial for the development of medullary thyroid carcinomas. Many of these mutations, particularly those leading to the activation of the MAPK pathway, are being actively explored as therapeutic targets for thyroid cancer. BRAFBRAF serine-threonine kinase belongs to the family of RAF proteins, which are intracellular effectors of the MAPK signaling cascade. Upon activation triggered by RAS binding and protein recruitment to the cell membrane, these kinases phosphorylate and activate MEK, which in turn activates ERK and consequent effectors of the MAPK cascade.Point mutations of the BRAF gene are found in B45% of thyroid papillary carcinomas.2,5 Virtually all point mutations involve nucleotide 1799 and result in a valine-to-glutamate substitution at residue 600 (V600E).6,7 BRAF V600E mutation leads to constitutive activation of BRAF kinase and the mechanism of activations has been recently elucidated. In the dephosphorylated, wild-type BRAF protein, the hydrophobic interactions between the activation loop and the ATP binding site maintain the protein in an inactive conformation. The V600E subs...

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Genotyping of an Italian papillary thyroid carcinoma cohort revealed high prevalence of BRAF mutations, absence of RAS mutations and allowed the detection of a new mutation of BRAF oncoprotein (BRAF^V599Ins)

Cited by 76 publications

References 27 publications

A molecular expression signature distinguishing follicular lesions in thyroid carcinoma using preamplification RT-PCR in archival samples

A molecular expression signature distinguishing follicular lesions in thyroid carcinoma using preamplification RT-PCR in archival samples

Signaling pathways in follicular cell-derived thyroid carcinomas

Thyroid carcinoma: molecular pathways and therapeutic targets

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