Genetic alterations and their relationship in the phosphatidylinositol 3-kinase/Akt pathway in thyroid cancer
Genetic alterations and their relationship in the phosphatidylinositol 3-kinase/Akt pathway in thyroid cancer
复制标题
DOI：
10.1158/1078-0432.ccr-06-1125
复制
发表时间：
2007-02-15
影响因子：
11.5
通讯作者：
Xing, Mingzhao
中科院分区：
文献类型：
--
作者：
Hou, Peng;Liu, Dingxie;Xing, Mingzhao
目的：探讨甲状腺肿瘤中磷脂酰肌醇 3 激酶 (PI3K)/Akt 通路遗传改变的总体发生情况和关系，并探讨该通路作为甲状腺癌治疗靶点的范围。实验设计：我们在一系列原发性甲状腺肿瘤中集体检查了该通路中的主要遗传改变及其关系，包括 PIK3CA 拷贝数增加和突变、Ras 突变和 PTEN 突变。 81 例良性甲状腺腺瘤 (BTA) 中的 25 例 (31%)、86 例滤泡性甲状腺癌 (FTC) 中的 47 例 (55%)、86 例乳头状甲状腺癌 (PTC) 中的 21 例 (24%) 以及 50 例甲状腺未变性癌 (ATC) 中的 29 例 (58%) 中发现了任何这些基因改变，其中 FTC 和 ATC 最常含有这些基因改变。 PIK3CA 拷贝增益与 PIK3CA 蛋白表达增加相关。在 BTA、FTC 和 PTC 中观察到这些基因改变之间的相互排斥性，表明它们中的每一个通过 PI3K/Akt 通路在分化的甲状腺肿瘤的肿瘤发生中发挥独立的作用。然而，随着从分化型肿瘤向未分化型 ATC 的进展，这些基因改变的共存现象越来越多。它们与 BRAF 突变的共存在 PTC 和 ATC 中也很常见。 结论：数据提供了强烈的遗传暗示，即 PI3K/Akt 通路的异常激活在甲状腺肿瘤发生中发挥着广泛作用，特别是在 FTC 和 ATC 中，并且随着该通路遗传改变的积累，促进 BTA 进展为 FTC 和 ATC。 PI3K/Akt 通路相关基因改变和 BRAF 突变的共存可能促进 PTC 进展为 ATC。因此，PI3K/Akt 通路可能是甲状腺癌的主要治疗靶点。
Purpose: To investigate the overall occurrence and relationship of genetic alterations in the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in thyroid tumors and explore the scope of this pathway as a therapeutic target for thyroid cancer.Experimental Design: We examined collectively the major genetic alterations and their relationship in this pathway, including PIK3CA copy number gain and mutation, Ras mutation, and PTEN mutation, in a large series of primary thyroid tumors.Results: Occurrence of any of these genetic alterations was found in 25 of 81 (31%) benign thyroid adenoma (BTA), 47 of 86 (55%) follicular thyroid cancer (FTC), 21 of 86 (24%) papillary thyroid cancer (PTC), and 29 of 50 (58%) anaplastic thyroid cancer (ATC), with FTC and ATC most frequently harboring these genetic alterations. PIK3CA copy gain was associated with increased PIK3CA protein expression. A mutual exclusivity among these genetic alterations was seen in BTA, FTC, and PTC, suggesting an independent role of each of them through the PI3K/ Akt pathway in the tumorigenesis of the differentiated thyroid tumors. However, coexistence of these genetic alterations was increasingly seen with progression from differentiated tumor to undifferentiated ATC. Their coexistence with BRAF mutation was also frequent in PTC and ATC.Conclusions: The data provide strong genetic implication that aberrant activation of PI3K/Akt pathway plays an extensive role in thyroid tumorigenesis, particularly in FTC and ATC, and promotes progression of BTA to FTC and to ATC as the genetic alterations of this pathway accumulate. Progression of PTC to ATC may be facilitated by coexistence of PI3K/Akt pathway- related genetic alterations and BRAF mutation. The PI3K/Akt pathway may thus be a major therapeutic target in thyroid cancers.