Hou Peng, Liu Dingxie, Shan Yuan, Hu Shuiying, Studeman Kimberley, Condouris Stephen, Wang Yangang, Trink Ariel, El-Naggar Adel K, Tallini Giovanni, Vasko Vasily, Xing Mingzhao
Division of Endocrinology and Metabolism, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
Clin Cancer Res. 2007 Feb 15;13(4):1161-70. doi: 10.1158/1078-0432.CCR-06-1125.
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.
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.
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.
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.
研究磷脂酰肌醇3激酶（PI3K）/Akt通路基因改变在甲状腺肿瘤中的总体发生率及其相互关系，并探索该通路作为甲状腺癌治疗靶点的范围。
我们在一大系列原发性甲状腺肿瘤中，共同检测了该通路中的主要基因改变及其相互关系，包括PIK3CA拷贝数增加和突变、Ras突变以及PTEN突变。
在81例良性甲状腺腺瘤（BTA）中有25例（31%）、86例滤泡状甲状腺癌（FTC）中有47例（55%）、86例乳头状甲状腺癌（PTC）中有21例（24%）以及50例间变性甲状腺癌（ATC）中有29例（58%）发现了这些基因改变中的任何一种，其中FTC和ATC最常出现这些基因改变。PIK3CA拷贝数增加与PIK3CA蛋白表达增加相关。在BTA、FTC和PTC中，这些基因改变之间存在相互排斥性，表明它们各自通过PI3K/Akt通路在分化型甲状腺肿瘤的发生发展中发挥独立作用。然而，随着肿瘤从分化型向未分化型ATC进展，这些基因改变的共存情况越来越常见。在PTC和ATC中，它们与BRAF突变的共存也很常见。
数据提供了有力的遗传学证据，表明PI3K/Akt通路的异常激活在甲状腺肿瘤发生中起广泛作用，尤其是在FTC和ATC中，并且随着该通路基因改变的积累，促进BTA向FTC以及向ATC进展。PI3K/Akt通路相关基因改变与BRAF突变的共存可能促进PTC向ATC进展。因此，PI3K/Akt通路可能是甲状腺癌的主要治疗靶点。
