Highly prevalent genetic alterations in receptor tyrosine kinases and phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways in anaplastic and follicular thyroid cancers
Highly prevalent genetic alterations in receptor tyrosine kinases and phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways in anaplastic and follicular thyroid cancers
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DOI：
10.1210/jc.2008-0273
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发表时间：
2008-08-01
影响因子：
5.8
通讯作者：
Xing, Mingzhao
中科院分区：
文献类型：
--
作者：
Liu, Zhi;Hou, Peng;Xing, Mingzhao
内容：受体酪氨酸激酶（RTK）和磷脂酰肌醇3-激酶（PI 3 K）/Akt和MAPK通路的遗传改变在间变性和滤泡性甲状腺癌[间变性甲状腺癌（ATC），滤泡性甲状腺癌（FTC）]中尚未完全确定。目的：本研究的目的是探索这些通路参与ATC的广泛遗传基础。设计：我们检查了这些通路中大量基因的突变和拷贝数增加以及ERK（p-ERK）和Akt的相应磷酸化。我们发现RTK基因的频繁拷贝增加，包括EGFR、PDGFR α和β、VEGFR 1和2、KIT和MET，以及PIK 3Ca、PIK 3Cb、和PI 3 K/Akt通路中的PDK 1基因。Ras、PIK 3Ca、PTEN和BRAF基因突变和RET/PTC重排在ATC中常见，而PDK 1、Akt 1、Akt 2和RTK基因突变在ATC中不常见。总体而言，46/48例ATC（95.8%）至少有一个遗传变异，37/48例ATC（77.1%）中有两个或两个以上的遗传变异共存。这些遗传改变在FTC中不太常见。48例ATC中有39例（81.3%）同时存在PI 3 K/Akt和MAPK信号通路的基因改变。RTK基因拷贝数的增加优先与p-Akt相关，表明它们在激活PI 3 K/Akt通路中起主导作用。Akt的磷酸化在FTC中远比p-ERK常见，并且两者在ATC中相对常见并且经常共存。结论：在ATC和FTC中，RTK和PI 3 K/Akt和MAPK通路的遗传改变是非常普遍的，这些信号通路的广泛作用以及针对ATC和FTC，特别是前者的治疗的发展提供了强有力的遗传基础。
Context: Genetic alterations in receptor tyrosine kinases (RTKs) and phosphatidylinositol 3-kinase (PI3K)/Akt and MAPK pathways have not been fully defined in anaplastic and follicular thyroid cancers [ anaplastic thyroid cancer (ATC), follicular thyroid cancer (FTC)].Objective: The objective of the study was to explore a wide-range genetic basis for the involvement of these pathways in ATC.Design: We examined mutations and copy number gains of a large panel of genes in these pathways and corresponding phosphorylation of ERK (p-ERK) and Akt.Results: We found frequent copy gains of RTK genes, including EGFR, PDGFR alpha and -beta, VEGFR1 and 2, KIT, and MET and in PIK3Ca, PIK3Cb, and PDK1 genes in the PI3K/Akt pathway. Mutations of Ras, PIK3Ca, PTEN, and BRAF genes and RET/PTC rearrangements were common, whereas mutations in PDK1, Akt1, Akt2, and RTK genes were uncommon in ATC. Overall, 46 of 48 ATC (95.8%) harbored at least one genetic alteration, and coexistence of two or more was seen in 37 of 48 ATC (77.1%). These genetic alterations were somewhat less common in FTC. Genetic alterations that could activate both the PI3K/Akt and MAPK pathways were found in 39 of 48 ATC (81.3%). RTK gene copy gains were preferentially associated with p-Akt, suggesting their dominant role in activating the PI3K/Akt pathway. The phosphorylation of Akt was far more common than p-ERK in FTC, and both were relatively common and often coexisted in ATC.Conclusions: Genetic alterations in the RTKs and PI3K/Akt and MAPK pathways are extremely prevalent in ATC and FTC, providing a strong genetic basis for an extensive role of these signaling pathways and the development of therapies targeting these pathways for ATC and FTC, particularly the former.