Activating BRAF and PIK3CA mutations cooperate to promote anaplastic thyroid carcinogenesis.
Activating BRAF and PIK3CA mutations cooperate to promote anaplastic thyroid carcinogenesis.
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DOI：
10.1158/1541-7786.mcr-14-0158-t
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发表时间：
2014-07
期刊：
影响因子：
--
通讯作者：
McMahon M
中科院分区：
文献类型：
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作者：
Charles RP;Silva J;Iezza G;Phillips WA;McMahon M
甲状腺恶性肿瘤是最常见的内分泌肿瘤。在各种组织学亚型中，间变性甲状腺癌（ATC）代表了所有病例的一个子集，但在甲状腺癌相关死亡率中占很大比例。事实上，ATC被认为是更具侵略性和难以治疗的癌症形式之一。迄今为止，缺乏相关的模型系统来严格评估在人类ATC中检测到的签名遗传异常如何有助于疾病的发病机制。BRAF原癌基因的突变激活在约40%的甲状腺乳头状癌（PTC）和25%的ATC中检测到。此外，在ATC中，突变的BRAF经常与PI3-激酶的p110催化亚基（PIK3CA）中的功能获得性突变或p53（TP53）或PTEN肿瘤抑制因子中的功能丧失性改变相结合。使用BRAFV600E的条件性甲状腺细胞特异性表达的小鼠，我们先前开发了PTC模型。然而，与人类一样，BRAFV 600 E诱导的小鼠PTC是惰性的，不会导致终末期疾病的快速发展。在这里，我们使用携带PIK3CA的条件等位基因的小鼠来证明，尽管突变激活的PIK3CAH1047 R不能单独驱动转化，但当与甲状腺细胞中的BRAFV 600 E组合时，这导致小鼠中致死性ATC的发展。结合起来，这些数据表明BRAFV 600 E与PIK3CAH1074 R或与肿瘤抑制因子PTEN的沉默合作，以促进间变性甲状腺癌的发展。
Thyroid malignancies are the most common type of endocrine tumors. Of the various histological sub-types, anaplastic thyroid carcinoma (ATC) represents a subset of all cases but is responsible for a significant proportion of thyroid cancer related mortality. Indeed, ATC is regarded as one of the more aggressive and hard to treat forms of cancer. To date, there is a paucity of relevant model systems to critically evaluate how the signature genetic abnormalities detected in human ATC contribute to disease pathogenesis. Mutational activation of the BRAF proto-oncogene is detected in ~40% of papillary thyroid cancers (PTC) and in 25% of ATC. Moreover, in ATC, mutated BRAF is frequently found in combination with gain-of-function mutations in the p110 catalytic subunit of PI3-kinase (PIK3CA) or loss-of-function alterations in either the p53 (TP53) or PTEN tumor suppressors. Using mice with conditional, thyrocyte-specific expression of BRAFV600E, we previously developed a model of PTC. However, as in humans, BRAFV600E-induced mouse PTC is indolent and does not lead to rapid development of end-stage disease. Here we use mice carrying a conditional allele of PIK3CA to demonstrate that, although mutationally activated PIK3CAH1047R is unable to drive transformation on its own, when combined with BRAFV600E in thyrocytes, this leads to development of lethal ATC in mice. Combined, these data demonstrate that the BRAFV600E cooperates with either PIK3CAH1074R or with silencing of the tumor suppressor PTEN, to promote development of anaplastic thyroid cancer.