BRAFV600E mutation in anaplastic thyroid carcinomas and their accompanying differentiated carcinomas

Abstract

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...

BRAF Mutation in Papillary Thyroid Cancer: Pathogenic Role, Molecular Bases, and Clinical Implications

“…Some studies also found a correlation of BRAF mutation with high-risk clinicopathological characteristics of PTC within specific subtypes, such as conventional PTC (66,68,71) and follicular variant PTC (74). Several studies showed that PTC components often existed in BRAF mutation-harboring ATC tumors and, in such cases, the PTC and ATC components usually both harbored BRAF mutation (76,(93)(94)(95). This suggests that BRAF mutation may play a role in promoting the progression of PTC to ATC.…”

The Variable Presentations of Anaplastic Spindle Cell Squamous Carcinoma Associated with Tall Cell Variant of Papillary Thyroid Carcinoma

“…BRAF mutations may be enriched in TCV PTC; one study demonstrated that all six TCV PTC cases harbored the BRAF mutation (20). In addition, anaplastic carcinomas (two of three cases, and three of nine cases) with adjacent TCV PTC also tested positive for the BRAF mutation (20,21). However, BRAF mutations are seen at all stages of PTC, including papillary microcarcinomas, indicating that additional mutations must take place for dedifferentiation to occur.…”

Fetal cell carcinogenesis of the thyroid: A modified theory based on recent evidence [My Opinion]

“…RET/PTC and PAX8-PPARγ1 rearrangements are observed in a high prevalence of differentiated carcinomas but they are not detected in anaplastic carcinomas [13,14]. Furthermore, in five major studies carried out in Japan targeting patients with similar ethnic and environmental backgrounds, BRAF mutations were found in 39.7 % (378 out of 951) of papillary carcinomas, but only 18.1 % (6 out of 33) of anaplastic carcinomas, even though papillary carcinoma occupies about 90% of differentiated thyroid carcinoma in Japan [15][16][17][18][19].…”