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

Abstract

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. Materials and 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.

Functional impact of a germline RET mutation in alveolar rhabdomyosarcoma

“…The presence of a known, characterized oncogenic germline RET mutation ( Schuffenecker et al 1998 ; Masbi et al 2014 ) led to the hypothesis that clinical RET inhibitors, as monotherapy or in combination, would be promising treatment options for RET -mutant aRMS. To test this hypothesis, we created synthetic mutant RET cell models mimicking the genotype of the index case patient.…”

“…RET mutations occur in 1.8% of tumors across disparate disease types ( Kato et al 2017 ), and the PAX3:FOXO1 fusion occurs in 55% of ARMS cases ( Marshall and Grosveld 2012 ). The RET C634F mutation is associated with Multiple Endocrine (MEN) Type 2 and has well established oncogenic potential ( Schuffenecker et al 1998 ; Zhou et al 2007 ; Masbi et al 2014 ). Prior reports demonstrate metastatic PAX3:FOXO1 aRMS in a 13-yr-old male ( Agarwal et al 1997 ; Jones et al 2010 ) with familial MEN Type 2A induced by RET V804M mutation, a patient genotypically and phenotypically reminiscent of the index patient.…”

RET Proto Oncogene Mutation Detection and Medullary Thyroid Carcinoma Prevention

“…The mutations for MEN2A are mostly located in exon 10, including codons 609, 611, 618, and 620 (10-15%), and exon 11, including codons 630 and 634 (80-85%) (Donis-Keller et al, 1993;Mulligan et al, 1993;Eng et al, 1996). Hyperparathyroidism in MEN2A shows a strong association with the presence of a mutation in codon 634 and C634R in particular (Eng et al, 1996;Hedayati et al, 2006;Alvandi et al, 2011;Masbi et al, 2014). Other uncommon mutations in the intracellular TK domain have also been reported in MEN2A kindred (Marx and Stratakis, 2005;Hoff and Hoff, 2007).…”

Genetics and epigenetics of myelodysplastic syndromes and response to drug therapy: new insights

“…Similarly, in silico modeling approaches are used to develop cellular and genetic models. 93,94 The integration of computer-based modeling approaches into routine techniques can improve detection of cancer and result in the so-called computer-aided diagnostic models. These approaches have been dramatically used in various cancer predictions even in hematologic malignancies such as myeloma.…”