Clinical Implication of Hot SpotBRAFMutation, V599E, in Papillary Thyroid Cancers

Abstract

Activating mutations in the BRAF kinase gene have recently been reported in human cancers. The aim of the present study was to determine the frequency of BRAF mutations in thyroid cancer and their correlation with clinicopathological parameters. We analyzed exons 11 and 15 of BRAF gene in six human thyroid cancer cell lines and 207 paraffin-embedded thyroid tumor tissues. A missense mutation was found at T1796A (V599E) in exon 15 in four of the six cell lines and 51 of 207 thyroid tumors (24.6%; 0 of 20 follicular adenoma, 0 of 11 follicular carcinoma, 49 of 170 papillary carcinomas, and 2 of 6 undifferentiated carcinomas). Activation of MAPK kinase-MAPK pathway was observed in cell lines harboring BRAF mutation. BRAF mutation-associated enhanced cell growth was suppressed by MAPK kinase inhibitor, U0126. Examination of 126 patients with papillary thyroid cancer showed that BRAF mutation correlated significantly with distant metastasis (P = 0.033) and clinical stage (P = 0.049). Our results indicate that activating mutation of BRAF gene could be a potentially useful marker of prognosis of patients with advanced thyroid cancers.

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

“…[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%.…”

“…1-3). All of the papillary thyroid carcinomas from young patients are shown in the lower three rows (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). For case 3, analysis of both the primary papillary thyroid carcinoma (3P) and its metastatic implant (3M) are shown.…”

“…This hot spot was chosen because the reported BRAF-activating mutations in thyroid carcinomas occur almost exclusively at this position. 11,12,14 PCR primer sequences were designed to amplify a 102 bp fragment of exon 15 (5 0 -GAA GAC CTC ACA GTA AAA ATA GGT GA-3 0 , and 5 0 -CCA CAA AAT GGA TCC AGA CA-3 0 ). PCR amplification was performed using 100 ng of tumor sample DNA as template.…”

“…1,5 A better understanding of the genetic alterations underlying thyroid tumorigenesis may help explain these differences in clinical behavior. Whether BRAF mutations directly contribute to the more aggressive nature of adult papillary thyroid carcinoma remains to be established, but Namba et al 12 have recently identified BRAF mutations as a marker of advanced tumor stage.…”

“…Instead, the most frequent genetic alteration is mutational activation of the BRAF oncogene. [9][10][11][12][13] The RET and BRAF oncogenes represent tandem signaling effectors along the mitogen-activated protein kinase pathway. Activation of RET and BRAF induces constitutive activation of the mitogen-activated protein kinase pathway, but their individual roles in thyroid tumorigenesis are mutually exclusive, not cooperative: A papillary thyroid carcinoma usually harbors a RET/PTC translocation or a BRAF mutation, but not both.…”