Molecular profiling of aggressive thyroid carcinoma: comprehensive validation of genetic markers with tissue microarray and correlation with pathologic features and angiogenesis-PRIN

The treatment of thyroid cancer that is unable to concentrate the radioiodine is problematic. The identification of novel molecular markers for the aggressive tumor phenotypes that are unresectable and/or refractory to radioiodine therapy is essential to optimize treatment and to find new therapeutic targets. The aim of this research proposal is to identify molecular markers of aggressive thyroid tumor behavior, using tumor profiling by immunohistochemistry and tissue microarrays (TMA). To this effect we plan to: 1) identify and collect formalin-fixed, paraffin-embedded (FFPE) samples of thyroid carcinomas associated with aggressive features and suitable control tumors with matching clinicopathologic characteristics and follow up; 2) construct TMA with FFPE samples, obtained from the cases previously collected (see point 1 above), for immunohistochemical validation of relevant genetic markers identified by the other units; 3) genotype tumor subsets for their relevant molecular alterations, such as BRAF mutations and RET/PTC rearrangement (for papillary carcinoma), Ras mutations (for follicular carcinoma), p53 mutations (for poorly differentiated and anaplastic carcinoma); 4) define MAPK/ERK and PI3K/Akt pathway activation using immunohistochemistry, and angiogenesis by assessing microvessel density (MVD) and lymphatic vessel density (LVD), in thyroid carcinoma with aggressive clinicopathologic features.