The BRAFT1796A transversion is a prevalent mutational event in human thyroid microcarcinoma

Sedliarou, Ilya; Saenko, Vladimir; Lantsov, Dmitry; Rogounovitch, Tatiana; Namba, Hiroyuki; Abrosimov, Aleksandr; Lushnikov, E F; Kumagai, Atsushi; Nakashima, Masahiro; Meirmanov, Serik; Mine, Mariko; Hayashi, Tomayoshi; Yamashita, Shunichi

doi:10.3892/ijo.25.6.1729

Cited by 50 publications

(62 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The presence of BRAF mutation in both the differentiated PTC components and the undifferentiated components in ATC tumors suggest a role for BRAF mutation in disease progression (from well-differentiated PTC to undifferentiated ATC; Nikiforova et al 2003, Begum et al 2004, Cohen et al 2004. Consistent with this concept, a study by Sedliarou et al (2004) showed that when welldifferentiated tumors contained less-differentiated components, the prevalence of BRAF mutation was increased significantly. The BRAF mutation is not the only driving force for the formation of ATC, as many ATC tumors do not harbor this mutation; this latter group of ATCs is likely derived from FTC, which is negative for BRAF mutation , Cohen et al 2004.…”

Section: Introductionsupporting

confidence: 69%

“…The high frequency and specificity of BRAF mutation suggest that this mutation may play a fundamental role in the initiation of PTC tumorigenesis. This idea was supported by the presence of BRAF mutation in micro PTC , Sedliarou et al 2004. The presence of BRAF mutation in both the differentiated PTC components and the undifferentiated components in ATC tumors suggest a role for BRAF mutation in disease progression (from well-differentiated PTC to undifferentiated ATC; Nikiforova et al 2003, Begum et al 2004, Cohen et al 2004.…”

Section: Introductionsupporting

confidence: 54%

See 1 more Smart Citation

BRAF mutation in thyroid cancer

Xing¹

2005

Endocrine Related Cancer

1,169

976

View full text Add to dashboard Cite

Genetic alteration is the driving force for thyroid tumorigenesis and progression, based upon which novel approaches to the management of thyroid cancer can be developed. A recent important genetic finding in thyroid cancer is the oncogenic T1799A transversion mutation of BRAF (the gene for the B-type Raf kinase, BRAF). Since the initial report of this mutation in thyroid cancer 2 years ago, rapid advancements have been made. BRAF mutation is the most common genetic alteration in thyroid cancer, occurring in about 45% of sporadic papillary thyroid cancers (PTCs), particularly in the relatively aggressive subtypes, such as the tall-cell PTC. This mutation is mutually exclusive with other common genetic alterations, supporting its independent oncogenic role, as demonstrated by transgenic mouse studies that showed BRAF mutation-initiated development of PTC and its transition to anaplastic thyroid cancer. BRAF mutation is mutually exclusive with RET/PTC rearrangement, and also displays a reciprocal age association with this common genetic alteration in thyroid cancer. The T1799A BRAF mutation occurs exclusively in PTC and PTC-derived anaplastic thyroid cancer and is a specific diagnostic marker for this cancer when identified in cytological and histological specimens. This mutation is associated with a poorer clinicopathological outcome and is a novel independent molecular prognostic marker in the risk evaluation of thyroid cancer. Moreover, preclinical and clinical evaluations of the therapeutic value of novel specific mitogen-activated protein kinase pathway inhibitors in thyroid cancer are anticipated. This newly discovered BRAF mutation may prove to have an important impact on thyroid cancer in the clinic.Endocrine-Related Cancer (2005) 12 245-262

show abstract

Section: Introductionsupporting

confidence: 69%

Section: Introductionsupporting

confidence: 54%

BRAF mutation in thyroid cancer

Xing¹

2005

Endocrine Related Cancer

1,169

976

View full text Add to dashboard Cite

show abstract

“…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: 69%

“…[12][13][14][15] This mutation results in constitutive activation of the kinase, potentiates downstream effectors in the MAP kinase signaling pathway, and confers transforming properties in cell lines. 12,15,16 BRAF V600E has been detected in a variety of papillary thyroid neoplasms, including papillary microcarcinoma, and more recently, malignant struma ovarii, [17][18][19] implying that the activating mutation is critical in the initiation of papillary thyroid neoplasia. The additional molecular changes that promote tumor progression, however, are not well characterized, but mutations in other oncogenes and tumor suppressor genes and altered cell signaling, cell cycle regulation, and apoptosis have been described in clinicopathologically aggressive thyroid neoplasms.…”

mentioning

confidence: 99%

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

et al. 2011

View full text Add to dashboard Cite

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

show abstract

“…36 -38). 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).…”

Section: Discussionmentioning

confidence: 99%

Targeting BRAFV600E in thyroid carcinoma: therapeutic implications

Mitsiades

Negri

McMullan

et al. 2007

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

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.

show abstract

The BRAFT1796A transversion is a prevalent mutational event in human thyroid microcarcinoma

Cited by 50 publications

References 0 publications

BRAF mutation in thyroid cancer

BRAF mutation in thyroid cancer

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

Targeting BRAFV600E in thyroid carcinoma: therapeutic implications

Contact Info

Product

Resources

About