Zuo Hui, Nakamura Yasushi, Yasuoka Hironao, Zhang Ping, Nakamura Misa, Mori Ichiro, Miyauchi Akira, Kakudo Kennichi
Department of Pathology, Wakayama Medical University, Wakayama, Japan.
Pathol Int. 2007 Jan;57(1):12-20. doi: 10.1111/j.1440-1827.2007.02050.x.
The BRAF V600E mutation has been identified in a high proportion of papillary thyroid carcinoma (PTC). In cell lines and a transgenic mouse model it has been demonstrated that the mutation constitutively activates the mitogen-activated protein kinase (MAPK) pathway but in human PTC samples its effects remain unexamined. Herein the correlation of BRAF mutation and MAPK activation was examined in 42 human PTC samples. Activating mutations of the BRAF gene and all three RAS genes were detected by polymerase chain reaction-direct sequencing, and RET/PTC1 rearrangements were screened by nested reverse transcription-polymerase chain reaction. MAPK activation was assessed by immunohistochemistry and western blot analysis. Twenty-eight cases (66.7%) of BRAF V600E mutation, three cases (7.1%) of RET/PTC1 rearrangement but no cases of RAS genes mutation were identified. Activated MAPK was found in six cases (14.3%) with only two cases of mutant BRAF. In total 7.1% of PTC with BRAF mutation had activated MAPK. Furthermore, BRAF mutations were more prevalent in patients > or =45 years, but did not correlate with aggressive clinical behaviors. Absence of association between BRAF mutation and activation of MAPK pathway in PTC suggests the presence of mechanisms that downregulate MAPK activation.
在高比例的甲状腺乳头状癌（PTC）中已发现BRAF V600E突变。在细胞系和转基因小鼠模型中已证实，该突变可组成性激活丝裂原活化蛋白激酶（MAPK）途径，但在人类PTC样本中其作用仍未得到研究。在此，对42例人类PTC样本中BRAF突变与MAPK激活之间的相关性进行了研究。通过聚合酶链反应直接测序检测BRAF基因和所有三个RAS基因的激活突变，并通过巢式逆转录聚合酶链反应筛选RET/PTC1重排。通过免疫组织化学和蛋白质印迹分析评估MAPK激活情况。共鉴定出28例（66.7%）BRAF V600E突变、3例（7.1%）RET/PTC1重排，但未发现RAS基因突变病例。在6例（14.3%）中发现激活的MAPK，其中只有2例为BRAF突变型。BRAF突变的PTC中共有7.1%存在激活的MAPK。此外，BRAF突变在年龄≥45岁的患者中更为普遍，但与侵袭性临床行为无关。PTC中BRAF突变与MAPK途径激活之间缺乏关联表明存在下调MAPK激活的机制。
