Prevalence, Tumorigenic Role, and Biochemical Implications of Rare <i>BRAF</i> Alterations

Barollo, Susi; Pezzani, Raffaele; Cristiani, Andrea; Redaelli, Marco; Zambonin, Laura; Rubin, Beatrice; Bertazza, Loris; Zane, Mariangela; Mucignat‐Caretta, Carla; Bulfone, Alessandro; Pennelli, Gianmaria; Ide, Eric Casal; Pelizzo, Maria Rosa; Mantero, Franco; Moro, Stefano; Mian, Caterina

doi:10.1089/thy.2013.0403

Cited by 51 publications

(37 citation statements)

References 36 publications

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“…Genetic analysis showed a rare aminoacidic insertion in codon 599 of the BRAF gene (1797_1798insACA, T599insT: Although in this study and in cited reports (8,(10)(11)(12)(13)(14) all mutations lead to the same T599dup alteration at amino acid level, at DNA level they are described as an ACA duplication (11,12), and as an insertion of TAC between C and A in the other studies. In silico analysis, performed on BRAFV599ins and BRAFT599insT (9,12), indicates that mutations involving the P-loop make the active geometrical conformation more stable than the wild-type counterpart, causing an highly productive catalytic state. In vitro kinase assays carried out on BRAFV599ins and BRAFV600E (9) revealed a three-to-five-fold increase in the enzymatic activity (BRAF-induced phosphorylation of MEK and MAPK) of both mutants compared to BRAFWT.…”

Section: Case Reportcontrasting

confidence: 41%

“…Herein, we report a single case of primary cutaneous melanoma showing a mutation occurring in the P-loop activating site (c.1797_1798insACA, T599insT), which was not previously described in melanomas, but only rarely found in Pilocytic Astrocytoma (PA), Papillary Thyroid Carcinoma (PTC) and Anaplastic Thyroid Carcinoma (ATC) (8)(9)(10)(11). In silico and in vitro data indicate that rare and/or complex mutations in codons 599-601 increase kinase activity similarly to the typical V600E (8,9,12,13).…”

Section: Introductionmentioning

confidence: 83%

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Novel BRAF mutation in melanoma: A case report

et al. 2018

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Abstract. In melanoma, a number of specific genetic and genomic aberrations have been identified to be important in tumorigenesis. In particular, the mutant B-Raf proto-oncogene, Serine/Threonine kinase (BRAF) gene is the target of tailored therapy with kinase inhibitor molecules. Identification of the array of mutations in patients with melanoma will be useful in determining a genetic profile of the tumor with potential implications for treatment decisions. A rare aminoacidic insertion in codon 599 of the BRAF gene (c.1797_1798insACA, T599insT) was detected by using both direct (Sanger) sequencing and pyrosequencing techniques in a metastatic melanoma of a female elderly patient. As suggested in other clinical contexts including pilocytic astrocytoma, papillary thyroid carcinomas and anaplastic thyroid carcinomas, this unusual mutation may be associated with a modified spatial structure of activated P-loop, resulting in a constitutional activation of the BRAF protein. The patient died shortly following the test, thus no biological therapy was performed. Comparable data regarding treatment of melanoma patients with rare BRAF mutations is lacking, and the response to BRAF inhibitors requires further investigation. IntroductionMutations of BRAF oncogene are common in cutaneous melanomas, being found in as much as 50% of the total number of cases. Most mutations involve exon 15, exon 11 being interested in less than 1% of cases (1). V600E in exon 15 is by far the most common (2). This mutation modifies the spatial structure of activation P-loop, causing a 500-fold increase in BRAF kinase activity and facilitating the acquisition of secondary genetic events in cancer progression (3). Target therapy for cutaneous melanomas is focused on this mutation: small molecules (vemurafenib and dabrafenib) act as Tyrosine Kinase Inhibitors (TKIs), and interrupt the BRAF/MEK step in RAS/MEK/ERK pathway, inducing apoptosis in mutated cells (4). Less frequent BRAF mutations (5,6) with alterations in the same crucial site, such as Threonine599 and Serine601 (7), have been described. Herein, we report a single case of primary cutaneous melanoma showing a mutation occurring in the P-loop activating site (c.1797_1798insACA, T599insT), which was not previously described in melanomas, but only rarely found in Pilocytic Astrocytoma (PA), Papillary Thyroid Carcinoma (PTC) and Anaplastic Thyroid Carcinoma (ATC) (8-11). In silico and in vitro data indicate that rare and/or complex mutations in codons 599-601 increase kinase activity similarly to the typical V600E (8,9,12,13). Case reportΑ 88-year-old female was presented with large, ulcerated superficial spreading melanoma on the left cheek, including a nodular polypoid component, widely ulcerated, with regression arising from a radial growth phase pigmented macula. Histologic examination showed a T4 lesion, Clark level V, with invasion into the subcutaneous fat (Fig. 1A). Angiolymphatic and perineural invasion were also described and a mitotic rate of 20/mm 2 was detected. Melanoma cells w...

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Section: Case Reportcontrasting

confidence: 41%

Section: Introductionmentioning

confidence: 83%

Novel BRAF mutation in melanoma: A case report

et al. 2018

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“…The classic c.1799T.A (V600E) mutation represents approximately 97% of BRAF alterations in PTC, while this mutant represents approximately 0.2% to 0.5% of PTCs. 6,9 To the best of our knowledge, the patient in this cohort represents the youngest reported to have such a mutation. Hou and colleagues 32 identified kinetic properties of the product of this BRAF mutation that resemble the V600E mutant with constitutive activation.…”

Section: Commentmentioning

confidence: 83%

“…6,9,31,32 The histologic appearance of this tumor is illustrated in the Figure, A and B. The classic c.1799T.A (V600E) mutation represents approximately 97% of BRAF alterations in PTC, while this mutant represents approximately 0.2% to 0.5% of PTCs.…”

Section: Commentmentioning

confidence: 99%

“…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.…”

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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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Uncommon BRAF mutations in the follicular variant of thyroid papillary carcinoma: New insights

Rossi

Martini

Bizzarro

et al. 2015

Cancer Cytopathology

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BACKGROUND: Mutational analysis is reshaping the practice of fine-needle aspiration cytology for the diagnosis of thyroid nodules. The v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) valine (V) to glutamic acid (E) substitution at codon 600 (BRAF V600E ) is the most effective diagnostic/prognostic marker and is used mainly for papillary thyroid carci- KEY WORDS: BRAF mutations; follicular neoplasms; follicular variant of papillary thyroid carcinoma; liquid-based cytology; papillary thyroid carcinoma.

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Prevalence, Tumorigenic Role, and Biochemical Implications of Rare BRAF Alterations

Cited by 51 publications

References 36 publications

Novel BRAF mutation in melanoma: A case report

Novel BRAF mutation in melanoma: A case report

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

Uncommon BRAF mutations in the follicular variant of thyroid papillary carcinoma: New insights

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