Predominant RET Germline Mutations in Exons 10, 11, and 16 in Iranian Patients with Hereditary Medullary Thyroid Carcinoma

Hedayati, Mehdi; Yeganeh, Marjan Zarif; Eslami, Sara Sheikhol; Barez, Shekoofe Rezghi; Rad, Laleh Hoghooghi; Azizi, Fereidoun

doi:10.4061/2011/264248

Cited by 32 publications

(38 citation statements)

References 32 publications

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“…Linkage disequilibrium analysis of the correlation of 5 of the 13 SNP in the RET gene showed that SNP G691S in exon 11 (rs1799939) and SNP S904S in exon 15 (rs1800863) were in complete linkage disequilibrium, which is consistent with a previous report [23] . SNP G691S and S904S are associated with the development of MTC in patients who carry germline mutations of the RET gene [26][27][28][29] .…”

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confidence: 81%

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Rare RET Variant p.D707E in a Chinese Pedigree with Hereditary Medullary Thyroid Carcinoma

Zhang

Li²,

Li³

et al. 2016

Pathobiology

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Background: Hereditary medullary thyroid carcinoma (HMTC) is thought to be associated with germline mutations of the RET proto-oncogene. Methods: We detected RET proto-oncogene germline mutations from a pedigree with HMTC in the east of China and investigated the characteristics of these mutations in this pedigree and their correlation with HMTC by direct sequencing of all 21 exons in the RET gene of all 46 subjects. Results and Conclusion: (1) Thirteen types of RET gene variants were detected in this pedigree. Of these, p.F285S in exon 4, c.854_855CA in exon 4, and p.D707E in exon 11 are reported for the first time in our study. (2) Both linkage disequilibrium analysis and logistic regression analysis showed a significant correlation between the p.D707E variant and HMTC (LOD = 3.69, OR = 4.413, p = 0.000167), indicating that this variant is a risk factor for medullary thyroid carcinoma (MTC). (3) The single-nucleotide polymorphisms (SNP) G691S in exon 11 (rs1799939), S904S in exon 15 (rs1800863), and rs2075912 and rs2565200 in the 3′-untranslated region of the RET proto-oncogene are in complete linkage disequilibrium (D' = 1, r² = 1); no correlation of these SNP and MTC was observed in this pedigree. (4) No hot-spot mutation of the RET proto-oncogene was detected in this pedigree. We drew the conclusion that the heterozygous nonsynonymous variant p.D707E in the RET proto-oncogene is rare, but it is a risk factor for hereditary MTC.

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confidence: 81%

“…Exons 11 and 13 are important functional regions of the RET gene [3,10,22,23] . Among the 13 variants in this pedigree, except p.D707E, p.G691S in exon 11, and p.L769L and p.V778I in exon 13 are located in the region that also codes ITK.…”

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confidence: 99%

Rare RET Variant p.D707E in a Chinese Pedigree with Hereditary Medullary Thyroid Carcinoma

Zhang

Li²,

Li³

et al. 2016

Pathobiology

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“…In USA the most common mutation in this gene was at codon 634 in patients with hereditary MTC (Moura et al, 2009). In Iran and China also the highest genetic variation and mutation was reported at codon 634 (Zhou et al, 2007;Hedayati et al, 2011). Thus, it seems that mutatio.n of codon 634 is the most common RET proto-oncogene mutation in MTC.…”

Section: Discussionmentioning

confidence: 98%

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

Masbi¹,

Mohammadi-Asl²,

Galehdari³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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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.

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“…By contrast, poorly differentiated (2,4) and anaplastic thyroid carcinoma account for 1-2% of thyroid malignancies. Medullary thyroid carcinoma (3%; MTC) is a malignancy of parafullicular C cells that are derived from neural crest and occurs in sporadic (75%) and hereditary (25%) types (5). This wide spectrum of progression has been closely linked with the pattern of cumulative genetic and epigenetic alterations, which are correlated with tumor differentiation, metastasis and invasion (6).…”

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confidence: 99%

Epigenetic modifications in human thyroid cancer

et al. 2014

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Thyroid carcinoma is the most common endocrine malignancy of the endocrine organs, and its incidence rate has steadily increased over the last decade. Over 95% of thyroid carcinoma is derived from follicular cells that have a spectrum of differentiation to the most invasive malignancy. The molecular pathogenesis of thyroid cancer remains to be clarified, although activating the and oncogenes have been well characterized. Increasing evidence from previous studies demonstrates that acquired epigenetic abnormalities participating with genetic alteration results in altered patterns of gene expression/function. Aberrant DNA methylation has been established in the CpG regions and microRNAs (miRNAs) expression profile recognized in cancer development. In the present review, a literature review was performed using MEDLINE and PubMed with the terms 'epigenetic patterns in thyroid cancer [or papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), medullary thyroid cancer (MTC), anaplastic thyroid cancer (ATC)]', 'DNA methylation in thyroid cancer (or PTC, FTC, MTC, ATC)', 'miRNA expression in thyroid cancer (or PTC, FTC, MTC, ATC)', 'epigenetic patterns in cancer' and the current understanding of epigenetic patterns in thyroid cancer was discussed.

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Predominant RET Germline Mutations in Exons 10, 11, and 16 in Iranian Patients with Hereditary Medullary Thyroid Carcinoma

Cited by 32 publications

References 32 publications

Rare RET Variant p.D707E in a Chinese Pedigree with Hereditary Medullary Thyroid Carcinoma

Rare RET Variant p.D707E in a Chinese Pedigree with Hereditary Medullary Thyroid Carcinoma

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

Epigenetic modifications in human thyroid cancer

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