Genetic Alterations and Their Relationship in the Phosphatidylinositol 3-Kinase/Akt Pathway in Thyroid Cancer

Abstract

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), 21of 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.

Array CGH demonstrates characteristic aberration signatures in human papillary thyroid carcinomas governed by RET/PTC

“…It is of note that 21 tumour-suppressor genes map within either the specific or the consistently altered regions. TIMP3 and PTEN have already been reported as tumour suppressors in thyroid tumours (Hu et al, 2006;Hou et al, 2007;Wang et al, 2007), while others are involved in a variety of different tumour types, for example, TGFBR3 and ANXA7 in prostate cancer (Torosyan et al, 2006;Dong et al, 2007), TNFSF15 and TUSC1 in lung cancer (Shan et al, 2004;Hou et al, 2005), SYK and Net1 in breast cancer (Repana et al, 2006;Huang et al, 2007), SLIT1, RSU1 and KLF6 in gliomas and glioblastosmas (Chunduru et al, 2002;Dickinson et al, 2004;Camacho-Vanegas et al, 2007), DBC1 in bladder cancer (Louhelainen et al, 2006), DEC1 in oesophageal squamous cell carcinomas (Yang et al, 2005), RB1 in retinoblastoma (Corson and Gallie, 2007) and LATS2 and DLEU7 in leukaemias (Hammarsund et al, 2004;Jimenez-Velasco et al, 2005). Some of these tumour suppressors have influence on the regulation of chromatin acetylation …”

An update on molecular biology of thyroid cancers

“…Akt-1 and Akt-2 were shown to be the most important genes in thyroid cancer [76]. It was previously determined that mutations, or amplification and genomic copy gain of the PI3KCA gene, encoding the catalytic subunit of PI3K, occur in thyroid tumors [77][78][79]. Decreased expression or inactivation of the tumor suppressor gene product PTEN and activation by RAS oncogenes have also been described to activate the PI3K/Akt signaling pathway and play a role in thyroid tumorigenesis [78][79][80].…”

AKT1 Inhibitory DNAzymes Inhibit Cell Proliferation and Migration of Thyroid Cancer Cells

“…All are structurally homologous and share similar mechanisms of activation, but exhibit distinct features (Hou et al, 2007;Liu R et al, 2012). AKT is overexpressed in a number of cancers, including colon, thyroid, pancreatic, ovarian and some steroid hormoneinsensitive breast cancers (Pitt, 2008).…”