Characterization of wild-type and mutated RET proto- oncogene associated with familial medullary thyroid cancer.
BACKGROUND
We aimed to assess RET proto-oncogene polymorphisms in three different Iranian families with medullary thyroid cancer (MTC), and performed molecular dynamics simulations and free energy stability analysis of these mutations.


METHODS
This study consisted of 48 patients and their first-degree relatives with MTC confirmed by pathologic diagnosis and surgery. We performed molecular dynamics simulations and 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.


RESULTS
The first family consisted of 27 people from four generations, in which nine had the C.G2901A (P.C634Y) mutation; the second family consisted of six people, of whom three had the C.G2901T (P.C634F) mutation, and the third family, who included 12 individuals from three generations, three having the C.G2251A (P.G691S) mutation. The automated 3D structure of RET protein was predicted using I-TASSER, and validated by various protein model verification programs that showed more than 96.3% of the residues in favored and allowed regions. The predicted instability indices of the mutated structures were greater than 40, which reveals that mutated RET protein is less thermo-stable compared to the wild-type form (35.4).


CONCLUSIONS
Simultaneous study of the cancer mutations using both in silico and medical genetic procedures, as well as onco-protein inhibitor binding considering mutation-induced drug resistance, may help in better overcoming chemotherapy resistance and designing innovative drugs.
Noor Genetic Diagnostic Laboratory, Ahvaz, Iran E-mail : Bioinfo2003@ajums.ac.ir.
Mohammad Hosein
MH
Masbi
Javad
J
Mohammadiasl
Hamid
H
Galehdari
Ahmad
A
Ahmadzadeh
Mohammad Amin
MA
Tabatabaiefar
Neda
N
Golchin
Vahid
V
Haghpanah
Fakher
F
Rahim
D018276:Carcinoma, Medullary / Q000151:congenital* / Q000235:genetics; D018278:Carcinoma, Neuroendocrine; D005091:Exons / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D011110:Polymorphism, Genetic / Q000235:genetics; D011446:Prospective Studies; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D011519:Proto-Oncogenes / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics*
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human