Xing M
Division of Endocrinology and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, 1830 E. Monument St/Suite 333 Baltimore, MD 21287, USA.
Endocr Relat Cancer. 2005 Jun;12(2):245-62. doi: 10.1677/erc.1.0978.
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.
基因改变是甲状腺肿瘤发生和进展的驱动力，基于此可开发甲状腺癌治疗的新方法。甲状腺癌最近一项重要的基因发现是BRAF（B型Raf激酶基因，BRAF）的致癌T1799A颠换突变。自2年前首次报道甲状腺癌中的这种突变以来，已取得了快速进展。BRAF突变是甲状腺癌中最常见的基因改变，约45%的散发性乳头状甲状腺癌（PTC）中存在该突变，尤其在相对侵袭性较强的亚型中，如高细胞型PTC。这种突变与其他常见基因改变相互排斥，支持其独立的致癌作用，转基因小鼠研究表明BRAF突变引发PTC的发生并向间变性甲状腺癌转变，从而证明了这一点。BRAF突变与RET/PTC重排相互排斥，并且在甲状腺癌中也与这种常见基因改变呈现出相反的年龄相关性。T1799A BRAF突变仅发生在PTC及其衍生的间变性甲状腺癌中，在细胞学和组织学标本中检测到时，是这种癌症的特异性诊断标志物。这种突变与较差的临床病理结果相关，是甲状腺癌风险评估中的一种新的独立分子预后标志物。此外，预计将对新型特异性丝裂原活化蛋白激酶途径抑制剂在甲状腺癌中的治疗价值进行临床前和临床评估。这一新发现的BRAF突变可能在临床上对甲状腺癌产生重要影响。
