Genetic analysis of <i>RET, GFRα1</i> and <i>GDNF</i> genes in Spanish families with multiple endocrine neoplasia type 2A

Gil, Laura; Azañedo, Marta; Pollán, Marina; Cristóbal, Eva; Arribas, Begoña; García-Albert, Luis; García-Sáiz, Alfredo; Maestro, M.L.; Torres, Antonio; Menárguez, Javier; Rojas, José M.

doi:10.1002/ijc.10298

Cited by 33 publications

(22 citation statements)

References 42 publications

(43 reference statements)

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“…Even in the presence of GDNF ligand, no valuable transforming activity different from RET-wt background was appreciated. 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: Discussionsupporting

confidence: 63%

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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

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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.

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Section: Discussionsupporting

confidence: 63%

“…The RET-G691S polymorphism has been suggested as a genetic modifier in MEN2A (Gil et al 2002), but this issue is controversial (Lesueur et al 2006). Conflicting results are also reported with regard to a possible role for this polymorphism in susceptibility to sporadic MTC ( (Fugazzola et al 2008) and references herein).…”

Section: Discussionmentioning

confidence: 93%

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

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“…The polymorphic G691S/S904S variant of RET has been implicated as a modifier factor on the age at which MEN 2A begins (Gil et al 2002, Robledo et al 2003, whereas the RETL769L polymorphism has been previously implicated as having an effect in the early development of hereditary MTC in a family with a mutation in exon 14 (Magalhaes et al 2004). However, we did not observe an association between the presence of these variants and clinical presentation of the disease in hereditary MTC.…”

Section: Discussionmentioning

confidence: 99%

The RET polymorphic allele S836S is associated with early metastatic disease in patients with hereditary or sporadic medullary thyroid carcinoma

Siqueira

Romitti²,

Rocha³

et al. 2010

Endocrine-Related Cancer

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The possible role of RET variants in modifying the natural course of medullary thyroid carcinoma (MTC) is still a matter of debate. Here, we investigate whether the RET variants L769L, S836S, and G691S/S904S influence disease presentation in hereditary or sporadic MTC patients. One hundred and two patients with hereditary MTC and 81 patients with sporadic MTC attending our institution were evaluated. The frequencies of RET polymorphisms in hereditary MTC were as follows: L769L, 17.3%; S836S, 7.95%; and S904S/G691S, 18.2%. No associations were observed between these polymorphisms and pheochromocytoma, hyperparathyroidism, lymph node, or distant metastasis. However, patients harboring the S836S variant were younger than those without this allele (17G8.2 vs 28.6G14.4 years, PZ0.01), suggesting that these patients had metastases at a young age. Accordingly, the cumulative frequency of local and/or distant metastases as estimated by Kaplan-Meier curves showed that lymph node and distant metastases occurred earlier in patients harboring the S836S variant (PZ0.003 and PZ0.026 respectively). The S836S allele frequency was higher in sporadic MTC patients than in controls (10.5 vs 3.1%, PZ0.01). Individuals harboring the S836S variant were younger (38.6G13.3 vs 48.5G16.7 years, PZ0.02) and showed a higher percentage of lymph node and distant metastases (PZ0.02 and PZ0.04 respectively). Kaplan-Meier estimates of lymph node and distant metastases yielded distinct curves for patients with or without the S836S allele (PZ0.002 and PZ0.001 respectively). Additional analyses using a COX regression model showed that the S836S variant was independently associated with metastatic disease (hazard ratio 2.82 (95% confidence interval 1.51-5.26), PZ0.001). In conclusion, the RET S836S variant is associated with early onset and increased risk for metastatic disease in patients with hereditary or sporadic MTC.

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“…15,16,23,43 Robledo et al, 15 for instance, observed that MEN2A patients homozygotes for the SNP A allele were in average 10 years younger than the others and that those younger than 20 years had higher risk of disease, a finding somehow confirmed also in sMTC younger than 45 years. However, the other studies selected for the meta-analysis could not detect any correlation between G691S and age 17,41 or gender, 17 although no details about the analyses performed are reported.…”

Section: Discussionmentioning

confidence: 88%

The involvement of the RET variant G691S in medullary thyroid carcinoma enlightened by a meta‐analysis study

Lantieri

Caroli

Ceccherini

et al. 2012

Intl Journal of Cancer

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Medullary thyroid carcinoma (MTC) is a rare tumor, partially explained by mutations in the rearranged during transfection (RET) proto-oncogene. The nonsynonymous RET polymorphism G691S has been reported as associated with MTC, but findings are discordant. We sought to clarify the role of G691S in MTCs through in silico analysis, genetic association in our patients and a meta-analysis with extensive literature revision. Ninety-three Italian patients were compared to 85 healthy individuals. Results were included in a meta-analysis together with 11 case-control association studies identified through PubMed, EMBASE and Web of Science, with a combined sample of 968 cases and 2,115 controls. No association of G691S with MTC was found in our sample; however, we observed an excess of homozygotes for the variant, significantly higher among females. The overall allelic association in the meta-analysis was significant under the fixed-effect model (odds ratio [OR] applied to the eight studies with available genotype frequencies, results were significant under both effect models (OR 5 2.016 and OR 5 2.022, p 5 0.0004). No heterogeneity was anymore detectable. In silico analyses on G691S confirmed a change of the phosphorylation pattern that might account for the enhanced signaling transduction previously reported for G691S in several cancers, thus also explaining its overrepresentation in MTCs. The G691S variant allele does increase the risk for MTC, with a recessive mechanism of action, apparently more evident among females.

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Genetic analysis of RET, GFRα1 and GDNF genes in Spanish families with multiple endocrine neoplasia type 2A

Cited by 33 publications

References 42 publications

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

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

The RET polymorphic allele S836S is associated with early metastatic disease in patients with hereditary or sporadic medullary thyroid carcinoma

The involvement of the RET variant G691S in medullary thyroid carcinoma enlightened by a meta‐analysis study

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