Association of PTEN Gene Methylation With Genetic Alterations in the Phosphatidylinositol 3-Kinase/AKT Signaling Pathway in Thyroid Tumors

BACKGROUND. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway plays an important role in thyroid tumorigenesis and progression. Genetic alterations, particularly PIK3CA amplification and mutations and ras mutations, are the major cause of aberrant activation of this pathway in thyroid tumors. Epigenetic silencing of the PTEN gene, a negative regulator of the PI3K/AKT pathway, also occurs in thyroid tumors, hut its relationship with genetic alterations in this pathway is unclear. METHODS. By using quantitative methylation-specific polymerase chain reaction, the authors examined PTFN methylation and its relationship with genetic alterations in the PI3K/AKT pathway in various types of thyroid tumors. RESULTS. The authors found PTEN methylation to become progressively higher from benign thyroid adenoma to follicular thyroid cancer and to aggressive anaplastic thyroid cancer, which harbored activating genetic alterations in the PI3K/AKT pathway correspondingly with a progressively higher prevalence. The association of PTEN methylation was seen with both overall genetic alterations and individual genetic alterations, particularly PIK3CA alterations and ras mutations, in the PI3K/AKT pathway within each of the 3 types of thyroid tumors. In contrast, no such relationship was observed for the tumor suppressor gene RASSF1A. CONCLUSIONS. The authors found an interesting association of PTEN methylation with the activating genetic alterations in the PI3K/AKT pathway in thyroid tumors. This finding is consistent with a model in which aberrant methylation and hence silencing of the PTEN gene, which coexists with activating genetic alterations of the PI3K/AKf pathway, may enhance the signaling of this pathway aberrantly activated by genetic alterations and hence contribute to tire progression of thyroid tumors. Cancer 2008;113:2440-7. (C) 2008 American Cancer Society.