Absence of RET Gene Point Mutations in Sporadic Thyroid C-Cell Hyperplasia

Section of Endocrinology, Department of Clinical and Biological Sciences, University of Turin, San Luigi Hospital, Orbassano, Italy.
Journal of Molecular Diagnostics (Impact Factor: 4.85). 05/2007; 9(2):214-9. DOI: 10.2353/jmoldx.2007.060166
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Progression from C-cell hyperplasia (CCH) to medullary thyroid carcinoma (MTC) has been demonstrated to date only in familial forms, whereas in nonfamilial MTC, such hypothesis is suggested by the rare concurrence of both lesions, although no epidemiological and molecular data are available to prove or disprove this event. Therefore, the clinical management of patients with sporadic CCH is controversial. To evaluate the malignant potential of sporadic CCHs, pure laser-microdissected C-cell populations of 24 CCH cases, either reactive or associated with nonfamilial MTC, were analyzed for MTC-associated protein neural cell adhesion molecule expression and RET point mutations in exons 10, 11, 15, and 16, by using immunohistochemistry and polymerase chain reaction-single-strand conformation polymorphism/heteroduplex electrophoresis/direct sequencing, respectively. No RET mutations were found in any of the 24 CCH cases, whereas M918T mutation was detected in three concomitant MTCs. Neural cell adhesion molecule was immunoreactive in the majority of CCH associated with MTC even in the absence of morphological atypia, but not in reactive forms. The absence of RET alterations in all cases of CCH examined supports the hypothesis that the development of MTC is independent of pre-existing CCH in the nonfamilial setting; thus, sporadic CCH should not be considered a risk factor for nonfamilial MTC.

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Available from: Fabio Orlandi, Mar 12, 2014
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    • "In Italy the highest and the lowest mutation rates of RET proto-oncogene mutation were belong to codons 804 and 634 in familial MTC, respectively, and in sporadic from was mutation at codon 918 (Pinna et al, 2007; Saggiorato et al., 2007). In Portugal and Czech Republic, the most common mutation was codon 918 for the sporadic form of MTC (Zedenius et al., 1994). "
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    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.
    Asian Pacific journal of cancer prevention: APJCP 03/2014; 15(5):2027-33. DOI:10.7314/APJCP.2014.15.5.2027 · 2.51 Impact Factor
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    • "A comparison of our data with those available in the literature on other Caucasians indicates that the common alteration from Cys634Gly in this study may represent a founder effect. Indeed it has been reported that Cys634Arg mutationthat is the most common mutation in MTC patients in many population—is related to parathyroid diseases [30]. However, this mutation is rare in our population (identified in one patient, only). "
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    ABSTRACT: Medullary thyroid carcinoma occurs in both sporadic (75%) and hereditary (25%) forms. The missense mutations of RET proto-oncogene in MTC development have been well demonstrated. To investigate the spectrum of predominant RET germline mutations in exons 10, 11, and 16 in hereditary MTC in Iranian population, 217 participants were included. Genomic DNAs were extracted from the leukocytes using the standard Salting Out/Proteinase K method. Mutation detection was performed through PCR-RFLP and DNA sequencing. In 217 participants, 43 missense mutations were identified in exons 10 (6%), 11 (13%), and 16 (0.9%). Moreover, a novel germline mutation was detected in exon 11 (S686N). Also four different polymorphisms were found in intron 16 in eight patients. The obtained data showed the frequency profile of RET mutations in Iranian individuals with MTC (19.8%). The most frequent mutation in our population was C634G whereas in most population it was C634R. Altogether, these results underline the importance of the genetic background of family members of any patient with MTC.
    Journal of Thyroid Research 06/2011; 2011:264248. DOI:10.4061/2011/264248
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    Der Onkologe 07/2010; 16(7):644-656. DOI:10.1007/s00761-010-1872-0 · 0.14 Impact Factor
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