Elucidation of thyroid carcinogenesis and clinical application of molecular targeting therapy

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In order to clarify the involvement of abnormalities of intracellular signaling pathway and genomic instability of thyroid carcinogenesis, we performed molecular analysis of related genes on thyroid cancers using operated thyroid tissues and cell culture systems. There were no specific abnormal genetic alterations on ARAF, RAPA1 and GNAQ on operated thyroid cancer tissues and cancer cell lines besides BRAF and RET?PTCs. The cell transformation assay suggested the involvement of ARAF abnormality in vitro, however, no ARAF mutation was proved in vivo. The data obtained suggested the relationship between DNA damage response and cell cycle regulation on thyroid cell transformation by irradiation. The molecular epidemiological study using Chernobyl samples suggested the involvement of FOXOE1 (TTF2) SNPs on genetic susceptibility on radiation-induced thyroid carcinogenesis although further confirmation is needed. Moreover, there were some disease-related SNPs of DNA damage response genes on thyroid carcinogenesis.In contrast clinical application of molecular targeting therapy has been hampered because of various barriers on clinical trial. The effectiveness of targeting restoration of p53 function has been proved but other molecules targeted are not yet applied yet. So we have tried the combination therapy of Gleevec and external radiation for the patients with advanced and anaplastic cancers with some partial response.