Characterization of Wild-Type and Mutated RET Proto-Oncogene Associated with Familial Medullary Thyroid Cancer

Abstract

<b>Background:</b> We aimed to assess RET proto-oncogene polymorphisms in three different Iranian familieswith medullary thyroid cancer (MTC), and performed molecular dynamics simulations and free energy stabilityanalysis of these mutations. Materials and <br/><b>Methods</b>: This study consisted of 48 patients and their first-degreerelatives with MTC confirmed by pathologic diagnosis and surgery. We performed molecular dynamics simulationsand free energy stability analysis of mutations, and docking evaluation of known RET proto-oncogene inhibitors,including ZD-6474 and ponatinib, with wild-type and mutant forms. <br/><b>Results</b>: The first family consisted of 27people from four generations, in which nine had the C.G2901A (P.C634Y) mutation; the second family consistedof six people, of whom three had the C.G2901T (P.C634F) mutation, and the third family, who included 12individuals from three generations, three having the C.G2251A (P.G691S) mutation. The automated 3D structureof RET protein was predicted using I-TASSER, and validated by various protein model verification programsthat showed more than 96.3% of the residues in favored and allowed regions. The predicted instability indicesof the mutated structures were greater than 40, which reveals that mutated RET protein is less thermo-stablecompared to the wild-type form (35.4). <br/><b>Conclusions</b>: Simultaneous study of the cancer mutations using both insilico and medical genetic procedures, as well as onco-protein inhibitor binding considering mutation-induceddrug resistance, may help in better overcoming chemotherapy resistance and designing innovative drugs.