BRAF mutations typical of papillary thyroid carcinoma are more frequently detected in undifferentiated than in insular and insular-like poorly differentiated carcinomas

Soares, Paula; Trovisco, Vítor; Rocha, Ana Sofia; Feijão, Tália; Rebocho, Ana Paula; Fonseca, Elsa; Castro, Inês; Cameselle-Teijeiro, José; Cardoso-Oliveira, Manuel; Sobrinho‐Simöes, Manuel

doi:10.1007/s00428-004-1018-0

Cited by 115 publications

(66 citation statements)

References 22 publications

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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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“…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.…”

mentioning

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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“…However, as noted above, an association between BRAF mutations and aggressive tumour behaviour has not been demonstrated in all populations, making the clinical relevance of this association uncertain. It is also of interest that the incidence of BRAF V600E mutations in undifferentiated anaplastic thyroid cancer is similar to that in well-differentiated early-stage tumours in several studies (Namba et al, 2003;Nikiforova et al, 2003;Begum et al, 2004;Soares et al, 2004;Trovisco et al, 2004;Trovisco et al, 2005) supporting the concept that some anaplastic thyroid cancers arise from more typical forms of PTC and suggesting that BRAF signalling may be functionally important in anaplastic thyroid cancers. These data also suggest that BRAF mutations may not be independently sufficient to induce dedifferentiation.…”

Section: Braf Mutations In Aggressive Ptcmentioning

confidence: 86%

Targeting BRAF in thyroid cancer

2006

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Activating mutations in the gene encoding BRAF are the most commonly identified oncogenic abnormalities in papillary thyroid cancer. In vitro and in vivo models have demonstrated that overexpression of activated BRAF induces malignant transformation and aggressive tumour behaviour. BRAF and other RAF kinases are frequently activated by other thyroid oncogenes and are important mediators of their biological effects including dedifferentiation and proliferation. Because current therapeutic options for patients with thyroid cancers that are aggressive and/or do not respond to standard therapies are limited, BRAF and its downstream effectors represent attractive therapeutic targets. In this review, data supporting a role for BRAF activation in thyroid cancer development and establishing the potential therapeutic efficacy of BRAF-targeted agents in patients with thyroid cancer will be reviewed.

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BRAF mutations typical of papillary thyroid carcinoma are more frequently detected in undifferentiated than in insular and insular-like poorly differentiated carcinomas

Cited by 115 publications

References 22 publications

Targeting BRAFV600E in thyroid carcinoma: therapeutic implications

Targeting BRAFV600E in thyroid carcinoma: therapeutic implications

BRAFV600E mutation in anaplastic thyroid carcinomas and their accompanying differentiated carcinomas

Targeting BRAF in thyroid cancer

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