Polymorphisms in the Initiators of RET (Rearranged during Transfection) Signaling Pathway and Susceptibility to Sporadic Medullary Thyroid Carcinoma

Cebrián, Arancha; Lesueur, Fabienne; Martin, Sophie G.; Leyland, Jean; Ahmed, Shahana; Luccarini, Craig; Smith, Paula; Luben, Robert; Whittaker, Joanne; Pharoah, Paul; Dunning, Alison M.; Ponder, Bruce A.J.

doi:10.1210/jc.2004-2449

Cited by 72 publications

(131 citation statements)

References 21 publications

Supporting

Mentioning

113

Contrasting

Unclassified

Order By: Relevance

“…The diagnosis of MTC was based on histopathological/immunohistochemistry findings and the absence of known germline RET point mutations in exons 8, 10, 11, or [13][14][15][16]. Clinical and laboratory data were collected for each individual.…”

Section: Patientsmentioning

confidence: 99%

“…It has also been described a higher frequency of intron 14 (IVS14-24) polymorphism in MTC patients with elevated serum calcitonin concentrations (23). On the other hand, a polymorphism in exon 2, codon 45, which encodes an alanine (AlaGCG/AlaGCA), occurred at a lower frequency among the cases of MTC and, according to the authors, it could confer a protective allele against the development of MTC (15).…”

Section: Introductionmentioning

confidence: 96%

“…Some studies have demonstrated that the RET variant G691S is more frequent in MTC patients than in the general population (14). The G691S/S904S variants were also associated with a 1.5-to 2.5-fold risk for the development of MTC (15). Patients with MTC younger than 30 years presented a higher frequency of the RET L769L variant than those diagnosed between 31 and 45 years (16).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Additive effect of RET polymorphisms on sporadic medullary thyroid carcinoma susceptibility and tumor aggressiveness

Ceolin

Siqueira²,

Ferreira³

et al. 2012

European Journal of Endocrinology

View full text Add to dashboard Cite

Objective: RET single nucleotide polymorphisms (SNPs) have been implicated in the pathogenesis and progression of medullary thyroid carcinoma (MTC). Here, we investigated the influence of multiple RET variants (G691S, L769L, S836S, and S904S) on the risk of MTC and tumor behavior. Design and methods: One hundred and seven MTC patients and 308 cancer-unaffected control individuals were included. SNPs were analyzed using Custom TaqMan Genotyping Assays. Haplotypes based on the combination of allelic variants were inferred using a Bayesian statistical method. Results: The minor allele frequencies in MTC patients were as follows: L769L: 28.0%, S836S: 8.9%, and G691S/S904S: 22.2%. The RET L769L and S836S SNPs were associated with increased risk of MTC (odds ratio (OR)Z1.95, 95% CI: 1.2-3.1, PZ0.005 and ORZ2.29, 95% CI: 1.2-4.5, PZ0.017 respectively). The adjusted OR for individuals harboring haplotypes with three or more polymorphic alleles was 3.79 (95% CI: 1.5-9.5; PZ0.004), indicating an additive effect of these variants on the risk for MTC. Among MTC patients, no significant associations were observed between RET variants and age of diagnosis or tumor size but serum calcitonin levels increased according to the number of risk alleles (PZ0.003). Remarkably, patients carrying haplotypes with three or four risk alleles had increased risk for lymph node and distant metastases at diagnosis (ORZ5.84, 95% CI: 1.1-31.2, PZ0.039). Further analysis using Kaplan-Meier model demonstrated that metastatic disease occurred earlier in individuals harboring multiple risk alleles. Conclusion: Our results demonstrated an additive effect of RET polymorphic alleles on the estimated risk of developing aggressive MTC.

show abstract

Section: Patientsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Additive effect of RET polymorphisms on sporadic medullary thyroid carcinoma susceptibility and tumor aggressiveness

Ceolin

Siqueira²,

Ferreira³

et al. 2012

European Journal of Endocrinology

View full text Add to dashboard Cite

show abstract

“…Whether RET polymorphisms can have a predisposing role in the pathogenesis of MTC is still controversial. Several studies have found a significantly higher frequency of such specific nonsynonymous polymorphism, p.G691S, in patients with MTC (29,30), though this has not been confirmed by others (31)(32)(33). The question is still debated with regard to CCH; indeed, in one recent study an overrepresentation of the p.G691S marker was observed in females with CCH in comparison with healthy controls (34), while in other studies no association with CCH, regardless of gender, could be demonstrated (31,32).…”

Section: Discussionmentioning

confidence: 92%

Uncommon association of germline mutations of RET proto-oncogene and CDKN2A gene

Foppiani

Forzano

Ceccherini

et al. 2008

European Journal of Endocrinology

View full text Add to dashboard Cite

Introduction: Calcitonin measurement is advised in the diagnosis of thyroid nodules, as it is an accurate marker of medullary thyroid carcinoma (MTC). C-cell hyperplasia (CCH)-induced hypercalcitoninemia cannot be distinguished from that induced by MTC, unless surgery is performed. Case: We report the clinical and biological features of a patient with a family history of cancer, including melanoma and pancreatic cancer, who had previously undergone surgery for melanoma. He presented the unusual association of papillary thyroid carcinoma (PTC), normocalcemic hyperparathyroidism, and hypercalcitoninemia with a pathological response to pentagastrin, which was histologically deemed secondary to CCH. Multiple endocrine neoplasia (MEN) 2A was diagnosed. RET gene analysis showed a p.V804M missense mutation in exon 14, a low-but variably penetrant defect found in both sporadic and MEN2A-associated MTC/CCH, and a p.G691S polymorphism in exon 11. Furthermore, the germline P48T mutation was found in the CDKN2A gene exon 1, which is known to be associated with melanoma and pancreatic cancer. The patient showed the uncommon coexistence of a germline mutation in two suppressor genes, RET and CDKN2A; this finding, deemed to be a mere coincidence, did not modify the phenotype expected by each single mutation. CCH associated with V804M RET mutation is a precancerous condition and surgery is recommended. In order to exclude MTC, surgery is advised in patients with a pathological calcitonin response to pentagastrin, in the absence of thyroid autoimmunity. CCH-induced hypercalcitoninemia can be associated with thyroid cancers other than MTC (e.g., PTC). Family history is important in scheduling specific genetic screening in high-risk patients and their relatives.

show abstract

“…Um aumento de 1,5 a 2,5 vezes no risco relativo para o desenvolvimento de CMT foi observado entre aqueles que apresentavam os polimorfismos no exon 11 (G691S), exon 15 (S904S) e exon 19 (STOP+388bp). De outro modo, o polimorfismo sinônimo no exon 2 (GCG→GCA), que codifica uma alanina (A45A), ocorreu em uma menor freqüência entre os casos de CMT e, segundo Cebrian, poderia representar um alelo protetor contra o desenvolvimento do CMT (63).…”

Section: Polimorfismos No Carcinoma Medular De Tireóideunclassified

Polimorfismos genéticos: implicações na patogênese do carcinoma medular de tireóide

Rocha

Magalhães

Maia

et al. 2007

Arq Bras Endocrinol Metab

View full text Add to dashboard Cite

RESUMOO carcinoma medular de tireóide (CMT) é uma neoplasia maligna rara, ocorrendo na forma esporádica ou hereditária. Mutações germinativas no proto-oncogene RET são responsáveis pelo CMT hereditário. No entanto, a maioria dos casos de CMT ocorre em indivíduos sem história familiar, na qual a patogênese da doença ainda é pouco compreendida. Os polimorfismos do gene RET são descritos na população geral assim como em pacientes com CMT. Embora estas variações alélicas aparentemente não confiram qualquer atividade transformadora no receptor RET, estudos sugerem que essas alterações genéticas podem modificar a suscetibilidade à doença e o fenótipo clínico em pacientes com CMT esporádico ou hereditário. Uma maior freqüência dos polimorfismos localizados nos exons 11 (G691S), 13 (L769L), 14 (S836S) e 15 (S904) é descrita em pacientes com CMT provenientes de países americanos e europeus. Na presente revisão, analisamos criticamente os resultados obtidos nos diferentes estudos e descrevemos a freqüência dos polimorfismos do RET em pacientes brasileiros com CMT esporádico. Medullary thyroid carcinoma (MTC) is a rare malignant neoplasia, which may occur on sporadic form or on a hereditary basis. Germ line mutations in the RET proto-oncogene is responsible for hereditary MTC. However, most MTC occur in individuals without family history where the pathogenesis is still unclear. Single nucleotide polymorphisms (SNPs) of the RET gene have been described in the general population as well as in patients with MTC. Even though these allelic variants do not seem to confer any transforming activity to the tyrosine kinase domain of the RET protein, cumulative studies suggest that they could modify disease susceptibility and clinical phenotype in patients with sporadic or hereditary MTC. Polymorphisms located in exons 11 (G691S), 13 (L769L), 14 (S836S), and 15 (S904S) seem to be over-represented in sporadic MTC patients from American and European countries. Here, we discuss the results obtained in different studies as well as describe the frequency of RET polymorphisms in Brazilian patients with sporadic MTC.

show abstract

Polymorphisms in the Initiators of RET (Rearranged during Transfection) Signaling Pathway and Susceptibility to Sporadic Medullary Thyroid Carcinoma

Cited by 72 publications

References 21 publications

Additive effect of RET polymorphisms on sporadic medullary thyroid carcinoma susceptibility and tumor aggressiveness

Additive effect of RET polymorphisms on sporadic medullary thyroid carcinoma susceptibility and tumor aggressiveness

Uncommon association of germline mutations of RET proto-oncogene and CDKN2A gene

Polimorfismos genéticos: implicações na patogênese do carcinoma medular de tireóide

Contact Info

Product

Resources

About