Specific polymorphisms in the RETproto-oncogene are over-represented in patients with Hirschsprung disease and may represent loci modifying phenotypic expression

Borrego, Salud; Sáez, María Eugenia; Ruiz, Agustı́n; Gimm, Oliver; López-Alonso, Manuel; Antiñolo, Guillermo; Eng, Charis

doi:10.1136/jmg.36.10.771

Cited by 140 publications

(129 citation statements)

References 20 publications

Supporting

Mentioning

103

Contrasting

Unclassified

Order By: Relevance

“…Moreover, it has been reported that a neutral germline sequence variance S836S RET may somehow predispose to sporadic MTC, especially those that harbour somatic M918T mutation . A highly significant association of RET polymorphisms, specifically the variant A45A, with Hirschsprung disease has also been observed (Borrego et al, 1999, Genetics and Genomics 2000; Fitze et al, 1999). Taking into account these and our present data, we suggest that the higher frequency of CCH observed in the irradiated thyroid glands of the patients bearing in their tumours a G691S RET SNP, may be an effect of the RET allele (or haplotype) on which the sequence variant has occurred.…”

Section: Discussionsupporting

confidence: 75%

“…It may be suggested that the GGT?AGT polymorphism causes the creation of a cryptic splice donor, splice acceptor or splice enhancer, therefore leading to an altered protein that may contribute to the development of C-cell hyperplasia. Similar mechanisms have been previously hypothesised in the cases of polymorphisms associated with sporadic MTC and Hirschsprung disease (Borrego et al, 1999;Fitze et al, 1999;Gimm et al, 1999). Unfortunately, RNA from our radio-induced thyroid tumours was not available to test this hypothesis.…”

Section: Discussionsupporting

confidence: 73%

See 1 more Smart Citation

Association of RET codon 691 polymorphism in radiation-induced human thyroid tumours with C-cell hyperplasia in peritumoural tissue

et al. 2002

View full text Add to dashboard Cite

The RET proto-oncogene encodes a protein structurally related to transmembrane receptors with an intracellular tyrosine kinase domain. In human thyroid gland, the RET proto-oncogene is normally expressed in parafollicular C-cells. Thyroid C-cell hyperplasia is associated with inherited medullary thyroid carcinomas and is considered as a pre-neoplastic stage of C-cells disease. It has also been observed in thyroid tissues adjacent to follicular and papillary carcinomas. In order to study the relationship between a misfunctioning of the RET proto-oncogene and the presence of C-cell hyperplasia, we compared a series of thyroid glands presenting sporadic or radiation-associated tumours, as well as samples of unrelated normal thyroid tissues, for alteration in exons 10 and 11 of the gene and for the presence or absence of C-cell hyperplasia. Here we report a significantly higher frequency of C-cell hyperplasia present in peritumoural thyroid tissues of radiation-induced epithelial thyroid tumours, than in peritumoural of sporadic thyroid tumours or in control normal thyroid tissues (P=0.001). A G691S RET polymorphism was present with a higher frequency in radiation-induced epithelial thyroid tumours (55%) than in sporadic tumours (20%) and in control normal thyroid tissues (15%). Interestingly, this polymorphism was associated in the majority (88%) of radiation-induced tumours with a C-cell hyperplasia in the peritumoural tissues. Several explanations for this association are discussed.

show abstract

Section: Discussionsupporting

confidence: 75%

Section: Discussionsupporting

confidence: 73%

Association of RET codon 691 polymorphism in radiation-induced human thyroid tumours with C-cell hyperplasia in peritumoural tissue

et al. 2002

View full text Add to dashboard Cite

show abstract

“…Regarding S904S polymorphism, also detected in the presented patient, strong co-segregation with G691S polymorphism has already been demonstrated (Gil et al 2002, Robledo et al 2003. Both polymorphisms have been shown to be under-represented in Hirschsprung's disease (HSCR, OMIM 142623) patients compared with controls, thus suggesting that they might protect against the development of HSCR (Borrego et al 1999). …”

Section: Discussionmentioning

confidence: 99%

Functional characterization of the MTC-associated germline RET-K666E mutation: evidence of oncogenic potential enhanced by the G691S polymorphism

Borrello¹,

Aiello²,

Peissel³

et al. 2011

Endocrine-Related Cancer

View full text Add to dashboard Cite

Activating mutations of RET, a gene encoding two isoforms of a tyrosine kinase receptor physiologically expressed in several neural crest-derived cell lineages, are associated with the inherited forms of medullary thyroid carcinoma (MTC). The identification and characterization of novel RET mutations involved in MTC is valuable, as RET gene testing plays a crucial role in the management of these patients. In an MTC patient, we have identified a germline c.1996AOG transition in heterozygosis leading to K666E substitution. In addition, the conservative S904S (c.2712COG) and the non-conservative functional G691S (c.2071GOA) polymorphisms have been identified. Through functional studies, we demonstrate for the first time that K666E is a gain-of-function mutation with oncogenic potential, based on its ability to transform NIH3T3 cells. It was not possible to define whether K666E is a de novo or inherited RET variant in the patient, as the family history was negative for MTC, and the carrier status of family members could not be tested. Our results, together with a recent report of co-segregation of the mutation in three MTC families, suggest that K666E is a causative MTC mutation. As we have shown that the same patient allele carries both K666E and G691S variants, the latter known to increase downstream RET signaling, a possible role for the G691S polymorphism has also been investigated. We have demonstrated that, although RET-G691S is not oncogenic per se, it enhances the transforming activity of the RET-K666E mutant, thus suggesting a modifier role for this functional polymorphism.

show abstract

“…Uma possível influência de polimorfismos do RET na doença de Hirschsprung (DH) foi também investigada (68). A DH é uma desordem genética que cursa com obstrução intestinal funcional secundária a aganglionose entérica e que pode estar associada a uma mutação inativadora do RET.…”

Section: Polimorfismos No Carcinoma Medular De Tireóideunclassified

“…Os autores observaram uma maior freqüência dos polimorfismos A45A e L769L comparada à população controle. De outro modo, os polimorfismos G691S e S904S apresentaram uma freqüência menor entre os pacientes com DH comparado aos controles (68).…”

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

Specific polymorphisms in the RETproto-oncogene are over-represented in patients with Hirschsprung disease and may represent loci modifying phenotypic expression

Cited by 140 publications

References 20 publications

Association of RET codon 691 polymorphism in radiation-induced human thyroid tumours with C-cell hyperplasia in peritumoural tissue

Association of RET codon 691 polymorphism in radiation-induced human thyroid tumours with C-cell hyperplasia in peritumoural tissue

Functional characterization of the MTC-associated germline RET-K666E mutation: evidence of oncogenic potential enhanced by the G691S polymorphism

Polimorfismos genéticos: implicações na patogênese do carcinoma medular de tireóide

Contact Info

Product

Resources

About