BRAF mutations in anaplastic thyroid carcinoma: implications for tumor origin, diagnosis and treatment
BRAF mutations in anaplastic thyroid carcinoma: implications for tumor origin, diagnosis and treatment
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DOI：
10.1038/modpathol.3800198
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发表时间：
2004-11-01
期刊：
影响因子：
7.5
通讯作者：
Westra, WH
中科院分区：
文献类型：
--
作者：
Begum, S;Rosenbaum, E;Westra, WH
甲状腺未分化癌是一种高度侵袭性的肿瘤。受影响的患者通常表现为晚期疾病，使用常规治疗方式治愈的希望很小。了解甲状腺未分化癌发生的遗传改变，如BRAF的突变激活，有助于阐明其与分化良好的甲状腺癌（即滤泡癌和乳头状癌）的关系，并有助于选择最有可能从针对BRAF的新治疗策略中获益的患者。我们使用一种新开发的检测方法检测了16例甲状腺未分化癌BRAF基因第1796位核苷酸的胸腺嘧啶（T）->腺嘌呤（A）错义突变，该方法采用了一种新的引物延伸方法（Mutector（R）检测）。其中7例甲状腺未分化癌与分化良好的甲状腺癌相关，这些也进行了评估。1796 T-->A突变在8例未分化甲状腺癌中检测到（50%），在4/5例相关乳头状甲状腺癌中检测到（80%），在0/2例相关滤泡状癌中检测到（0%）。在所有7例甲状腺未分化癌与分化良好的甲状腺癌相关的病例中，两种成分的BRAF状态是一致的。与乳头状甲状腺癌一样，相当比例的未分化甲状腺癌也存在BRAF突变。事实上，当甲状腺乳头状癌和甲状腺间变性癌同时发生时，它们始终具有相同的BRAF谱，支持许多甲状腺间变性癌实际上代表预先存在的分化良好的甲状腺癌的进行性恶性变性的观点。BRAF突变在通常被认为是一致致命的肿瘤中的高频率证明了评价抗BRAF治疗对未分化甲状腺癌患者的潜在益处是合理的。
Anaplastic thyroid carcinoma is a highly aggressive neoplasm. Affected patients typically present with advanced disease where there is little hope for cure using conventional therapeutic modalities. Understanding the genetic alterations underlying the development of anaplastic thyroid carcinoma, such as mutational activation of BRAF, could help clarify its relationship with well-differentiated forms of thyroid carcinoma (ie follicular and papillary carcinoma) and could help select patients most likely to benefit from novel therapeutic strategies targeting BRAF. We tested 16 anaplastic thyroid carcinomas for the thymine (T)--> adenine (A) missense mutation at nucleotide 1796 in the BRAF gene using a newly developed assay that employs a novel primer extension method (Mutector(R) assay). Seven of these anaplastic thyroid carcinomas arose in association with a well-differentiated thyroid carcinoma, and these were also evaluated. The 1796T-->A mutation was detected in eight (50%) of the anaplastic thyroid carcinomas, in four of five (80%) associated papillary thyroid carcinomas, and in zero of two (0%) associated follicular carcinomas. In all seven cases where anaplastic thyroid carcinoma arose in association with a well-differentiated thyroid carcinoma, BRAF status in the two components was concordant. Like papillary thyroid carcinoma, a significant percentage of anaplastic thyroid carcinomas also harbor BRAF mutations. Indeed, when papillary thyroid carcinoma and anaplastic thyroid carcinoma occur together, they consistently share the same BRAF profile, supporting the notion that many anaplastic thyroid carcinomas actually represent progressive malignant degeneration of a pre-existing well-differentiated thyroid carcinoma. The high frequency of BRAF mutations in a tumor that is generally regarded as uniformly fatal justifies evaluation of the potential benefits of anti-BRAF therapy for patients with anaplastic thyroid carcinoma.