BRAF T1796A Transversion Mutation in Various Thyroid Neoplasms

Xing, Mingzhao; Vasko, Vasily; Tallini, Giovanni; Larin, Alexander; Wu, Gujun; Udelsman, Robert; Ringel, Matthew D.; Ladenson, Paul W.; Sidransky, David

doi:10.1210/jc.2003-031488

Cited by 118 publications

(88 citation statements)

References 19 publications

(28 reference statements)

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“…Similarly, the BRAF V600E mutation has been frequently found in microcarcinomas of the thyroid (30), which suggests a role in tumor initiation rather than tumor progression. On the other hand, BRAF mutations are also found in poorly differentiated and anaplastic thyroid carcinomas, suggesting that they may play a role in their highly aggressive behavior (7,11,39,40). In the study of Nikiforova et al (7), all BRAF-mutant poorly differentiated and anaplastic carcinomas contained areas of preexisting papillary carcinoma, and the BRAF V600E mutation was present in both the well-differentiated and dedifferentiated components, suggesting that it may have contributed to the transition from PTC to anaplastic carcinoma.…”

Section: Discussionmentioning

confidence: 99%

Targeting BRAFV600E in thyroid carcinoma: therapeutic implications

Mitsiades

Negri

McMullan

et al. 2007

Molecular Cancer Therapeutics

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B-Raf is an important mediator of cell proliferation and survival signals transduced via the Ras-Raf-MEK-ERK cascade. BRAF mutations have been detected in several tumors, including papillary thyroid carcinoma, but the precise role of B-Raf as a therapeutic target for thyroid carcinoma is still under investigation. We analyzed a panel of 93 specimens and 14 thyroid carcinoma cell lines for the presence of BRAF mutations and activation of the mitogen-activated protein/ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway. We also compared the effect of a B-Raf small inhibitory RNA construct and the B-Raf kinase inhibitor AAL881 on both B-Raf wild-type and mutant thyroid carcinoma cell lines. We found a high prevalence of the T1799A (V600E) mutation in papillary and anaplastic carcinoma specimens and cell lines. There was no difference in patient age, B-Raf expression, Ki67 immunostaining, or clinical stage at presentation between wild-type and BRAF V600E specimens. Immunodetection of phosphorylated and total forms of MEK and ERK revealed no difference in their phosphorylation between wild-type and BRAF V600E patient specimens or cell lines. Furthermore, a small inhibitory RNA construct targeting the expression of both wild-type B-Raf and B-Raf V600E induced a comparable reduction of viability in both wild-type and BRAF V600E mutant cancer cells. Interestingly, AAL881 inhibited MEK and ERK phosphorylation and induced apoptosis preferentially in BRAF V600E -harboring cells than wild-type ones, possibly because of better inhibitory activity against B-Raf V600E . We conclude that B-Raf is important for the pathophysiology of thyroid carcinomas irrespective of mutational status. Small molecule inhibitors that selectively target B-Raf V600E may provide clinical benefit for patients with thyroid cancer.

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Section: Discussionmentioning

confidence: 99%

Targeting BRAFV600E in thyroid carcinoma: therapeutic implications

Mitsiades

Negri

McMullan

et al. 2007

Molecular Cancer Therapeutics

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“…[9][10][11][12][13][14][15][16][20][21][22] This variability is due in large part to the heterogeneous nature of tumors encompassed under the designation of papillary thyroid carcinoma, and likely reflects differences in: (1) phenotypic subtypes of papillary thyroid carcinoma, (2) exposure profiles, and (3) other yet undefined population-based characteristics such as patient age. We found, for example, that when the study sample is narrowed to sporadic conventional papillary thyroid carcinomas from adult patients over the age of 60, the prevalence of BRAF mutations approaches 90%.…”

Section: Discussionmentioning

confidence: 99%

Mutational activation of BRAF is not a major event in sporadic childhood papillary thyroid carcinoma

et al. 2005

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Papillary thyroid carcinoma may encompass a mixed group of neoplasms where divergence in clinical behavior may reflect distinct genetic alterations. For example, young patients with papillary thyroid carcinoma have a better prognosis than affected adults, and their carcinomas are much more likely to harbor chromosomal rearrangements involving the RET proto-oncogene. Mutational activation of the BRAF oncogene has recently been identified as the most common genetic alteration in papillary thyroid carcinoma, but little is known about its frequency as a function of patient age. We tested 20 papillary thyroid carcinomas from young patients ranging from 10 to 17 years of age for the thymine (T)-adenine (A) missense mutation at nucleotide 1796 in the BRAF gene using a newly developed assay that employs a novel primer extension method (Mutector s assay). The prevalence of BRAF mutation was compared with a larger group of papillary thyroid carcinomas from previously tested adult patients (420 years). BRAF mutations were not common in papillary thyroid carcinomas from young patients compared to their counterparts in adults (20 vs 77%; OR ¼ 13.3, 95% confidence interval (CI) ¼ 3.4-56.5; Po0.0001), but they become increasingly prevalent with advancing patient age (OR as a function of age at 10-year intervals ¼ 1.80 CI ¼ 1.33-2.44; Po0.001). Unlike papillary thyroid carcinomas that arise in adults, mutational activation of BRAF is not a major genetic alteration in papillary thyroid carcinomas that arise in young patients. The increasing frequency of BRAF mutations as a function of age could help account for the well documented but poorly understood observation that age is a relevant prognostic indicator for patients with papillary thyroid carcinoma. Modern Pathology (2005) 18, 898-902.

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“…When multi-step carcinogenesis is taken into account, a considerable number of anaplastic carcinomas with BRAF mutations should be found. In previous reports, however, the frequency of the BRAF mutation was only about 10% on average and ranged from 0 to 63% (Fukushima et al, 2003;Namba et al, 2003;Nikiforova et al, 2003;Begum et al, 2004;Soares et al, 2004;Xing et al, 2004;Quiros et al, 2005). Among these studies, some reported that the BRAF mutation is found frequently only in anaplastic carcinomas with a papillary carcinoma component, although these studies have examined only four or five cases.…”

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confidence: 94%

BRAFV600E mutation in anaplastic thyroid carcinomas and their accompanying differentiated carcinomas

et al. 2007

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Frequency of a BRAF V600E mutation in anaplastic thyroid carcinoma, which is thought to be derived mainly from papillary carcinoma by multi-step carcinogenesis, is much lower than that in papillary carcinomas. To clarify this phenomenon, we analysed BRAF V600E mutation in 20 cases of anaplastic carcinoma and 13 accompanying differentiated carcinomas. Among twenty cases of anaplastic carcinomas, nine and four accompanied papillary and follicular carcinomas, respectively. BRAF V600E mutation was found in four (20%) cases. BRAF V600E mutation was found in three of nine (33.3%), none of four and one of seven (14.3%) anaplastic carcinomas with papillary carcinoma, follicular carcinoma and without differentiated components, respectively. All three papillary carcinomas accompanied by anaplastic carcinoma with a BRAF V600E mutation were also shown to have a BRAF V600E mutation. In summary, BRAF V600E mutation was occasionally observed in anaplastic carcinomas with papillary carcinoma, and the low frequency of BRAF V600E mutation in anaplastic carcinoma was thought to be due to the low frequency of anaplastic carcinomas with papillary carcinoma. These findings raise a question about the classical model of anaplastic transformation and suggest some roles of thyroid cancer stem cells in the generation of anaplastic carcinoma. Thyroid carcinomas are thought to be generated from normal thyroid follicular cells (thyrocytes) by multi-step carcinogenesis (Farid et al, 1994). According to this hypothesis, anaplastic carcinomas are generated from both follicular and papillary carcinomas by genomic changes, such as mutations in TP53. Follicular carcinomas are generated from follicular adenomas, while papillary carcinomas are derived from some unknown precursor cells that are generated from normal thyrocytes. Recently, a somatic point mutation in the BRAF gene has been identified as the most common genetic event in papillary thyroid carcinoma . Most of the tumours with a mutation harboured a thymine-to-adenine transversion at nucleotide position 1799, which results in a valine-to-glutamic acid substitution at residue 600 (V600E). Previous reports indicated that BRAF mutations in thyroid tumours are generally restricted to papillary carcinoma, and usually there is no mutation in other types of well-differentiated thyroid cancers, including follicular carcinoma, Hürthle carcinoma and medullary carcinoma, as well as in benign thyroid tumours. The frequency of the mutations in papillary carcinomas is ranged from 29 to 83% of papillary carcinoma (Xing, 2005).It remains controversial whether this gene is also mutated in anaplastic thyroid carcinomas. In iodine-sufficient areas such as Japan, papillary carcinoma accounts for 90% of thyroid differentiated carcinomas and follicular carcinoma is rare (Hay, 1990). When multi-step carcinogenesis is taken into account, a considerable number of anaplastic carcinomas with BRAF mutations should be found. In previous reports, however, the frequency of the BRAF mutation was only about 10% on average...

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BRAF T1796A Transversion Mutation in Various Thyroid Neoplasms

Cited by 118 publications

References 19 publications

Targeting BRAFV600E in thyroid carcinoma: therapeutic implications

Targeting BRAFV600E in thyroid carcinoma: therapeutic implications

Mutational activation of BRAF is not a major event in sporadic childhood papillary thyroid carcinoma

BRAFV600E mutation in anaplastic thyroid carcinomas and their accompanying differentiated carcinomas

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