BRAF mutations in anaplastic thyroid carcinoma: implications for tumor origin, diagnosis and treatment

Begum, Shahnaz; Rosenbaum, Eli; Henrique, Rui; Cohen, Yoram; Sidransky, David; Westra, William H.

doi:10.1038/modpathol.3800198

Cited by 164 publications

(102 citation statements)

References 21 publications

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“…22 Early work suggested that altered BRAF is an adverse prognostic variable due to its association with unfavorable clinicopathological characteristics such as older age, male gender, and distant metastasis, and the high prevalence of BRAF mutations in the clinically aggressive tall-cell variant of papillary carcinoma and poorly differentiated and undifferentiated carcinomas. 16,18,21,22,49,51,52 However, BRAF V600E is also found in papillary thyroid microcarcinoma, a tumor that is typically benign and often discovered as an incidental finding, as well as in pre-malignant colorectal and nevocellular lesions, suggesting that an activating mutation in BRAF occurs early in the initiation of papillary thyroid neoplasia and may additionally confer susceptibility for malignant progression. 12,17,18,[53][54][55][56] Compatible with this interpretation, one of the three tumors harboring BRAF V600E in this study was clinically indolent, whereas two behaved aggressively.…”

Section: Discussionmentioning

confidence: 99%

Clinicopathological and molecular characterization of nine cases of columnar cell variant of papillary thyroid carcinoma

et al. 2011

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The majority of papillary thyroid carcinoma is indolent and associated with long-term survival. The columnar cell variant, however, is a rare subtype that is variable in biological behavior; some are clinically aggressive, whereas others are more clinically indolent. Tumor size, tumor circumscription, and encapsulation may influence the behavior of columnar cell carcinomas. Other variables including genetic changes and putative biomarkers associated with malignant growth have not been thoroughly examined in these neoplasms. In this study, nine cases of columnar cell variant of papillary thyroid carcinoma from three institutions were classified as clinically indolent or aggressive based on pathological features, clinical history, and outcome. Indolent tumors were typically small, circumscribed or encapsulated, and from younger female patients, whereas aggressive tumors were large, locally aggressive, associated with regional and distant metastasis, and from older male patients. The missense mutation, V600E in the BRAF oncogene (BRAF V600E ), was detected in three of nine of cases, of which two were clinically aggressive. Immunohistochemical evaluation of neoplasiaassociated markers showed increased nuclear cyclin D1 expression, elevated Ki-67 proliferation indices, and predominantly weak nuclear p53 staining in both indolent and aggressive tumors. Expression of b-catenin was largely restricted to a membranous pattern in both tumor types. Cytoplasmic expression of bcl-2 was overall mildly reduced in indolent neoplasms. Nuclear expression of estrogen and progesterone receptors was increased in both indolent and aggressive neoplasms, but was without sex-or age-related differences; however, whereas progesterone receptor expression was diffuse and strong in clinically indolent carcinomas, its expression was diminished in aggressive neoplasms. Recognition of the clinicopathological characteristics and the molecular and immunophenotypic features of the columnar cell variant of papillary thyroid carcinoma may aid in characterizing neoplasms that behave indolently or aggressively. Keywords: BRAF (BRAF V600E ); b-catenin; columnar cell variant; cyclin D1; papillary thyroid carcinoma Papillary thyroid carcinoma is a common endocrine neoplasm that is typically indolent and associated with long-term survival. This favorable biological behavior reflects the vast majority of conventional and histological variants of well-differentiated papillary thyroid carcinoma. However, a more aggressive tumoral growth characterizes a small subset that behaves more akin to poorly differentiated and undifferentiated thyroid carcinoma. Initially included in this group of aggressive neoplasms, the columnar cell variant is a rare subtype with variable biological behavior. Early reports described tumors with fast growth rates, aggressive local invasion, high rates of recurrence, early metastasis to regional lymph nodes and distant

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Section: Discussionmentioning

confidence: 99%

Clinicopathological and molecular characterization of nine cases of columnar cell variant of papillary thyroid carcinoma

et al. 2011

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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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“…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 mutations in anaplastic thyroid carcinoma: implications for tumor origin, diagnosis and treatment

Cited by 164 publications

References 21 publications

Clinicopathological and molecular characterization of nine cases of columnar cell variant of papillary thyroid carcinoma

Clinicopathological and molecular characterization of nine cases of columnar cell variant of papillary thyroid carcinoma

Targeting BRAFV600E in thyroid carcinoma: therapeutic implications

BRAFV600E mutation in anaplastic thyroid carcinomas and their accompanying differentiated carcinomas

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