Germline polymorphisms of RET and GFRA1 genes in patients with medullary thyroid carcinoma

Severskaya, N. V.; Saenko, Vladimir; Ilyin, A. A.; Chebotareva, Irina V.; Rumyantsev, P O; Исаев, П. А.; Medvedev, V. S.; Yamashita, Shunichi

doi:10.1134/s0026893306030046

Cited by 6 publications

(21 citation statements)

References 36 publications

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“…The allele frequencies of the RET polymorphisms are shown in Table 2. The observed SNP frequencies were similar to those reported in the literature (Elisei et al 2004, Wiench et al 2004, Baumgartner-Parzer et al 2005, Wohllk et al 2005, Severskaya et al 2010. Confirming previous studies, the two variants G691S and S904S were in linkage disequilibrium, and, therefore, to avoid redundant information, the results were grouped together and referred as G691S/S904S (Robledo et al 2003, Elisei et al 2004, Tamanaha et al 2009).…”

Section: Resultssupporting

confidence: 89%

“…However, they were unable to show an association between this variant and earlier age at onset in the large kindred cohort studied (Tamanaha et al 2009). A modulating effect of the combination of polymorphic L769L with wild-type S836S on the clinical outcome of hereditary MTC has also been described (Severskaya et al 2010). The segregation of RET V804L germline mutation and the S836S variant was reported in a Hungarian FMTC kindred comprising 80 individuals of four generations, but the co-existence of the V804L mutation and S836S polymorphism did not seem to aggravate the relatively low-risk disease phenotype (Patocs et al 2003).…”

Section: Discussionmentioning

confidence: 93%

“…Several SNPs of the RET proto-oncogene have been described in the general population as well as in patients with familial and sporadic MTC (Gimm et al 1999, Ruiz et al 2001, Elisei et al 2004, Severskaya et al 2010, Tamanaha et al 2009). Here, we have studied the frequency of the exonic RET polymorphisms L769L, S836S, and G691S/S904S in 17 MEN 2A families.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Resultssupporting

confidence: 89%

Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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 11 studies, in addition to this data, analyzed a number of patients ranging from 25 to 145, in line with the very low incidence of this cancer, while controls ranged between 25 12 and lack of symptoms of pheochromocytoma or hyperparathyroidism. 15,19,21 The 11 studies analyzed Portuguese, 14 Spanish, 15,18 Russian, 41 Cilean of Spanish origin 20 and Italian patients (our study). Gimm et al 21 and Bugalho et al 40 analyzed also individuals from United States, without specifying the ethnicity.…”

Section: Studies Selection and Characteristicsmentioning

confidence: 99%

“…Two other studies just specified ''Caucasian'' ethnicity. 12,17 Controls were unaffected individuals, ethnically 12,14,17,18,20,21,41 or region 13,14 matched to the cases in most of the articles. Three studies did not specify the ethnicity of either controls 15 or samples and controls.…”

Section: Studies Selection and Characteristicsmentioning

confidence: 99%

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 risk association of CDKN1A and RET gene SNPs with medullary thyroid carcinoma: Results from the largest MTC cohort and meta‐analysis

et al. 2019

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Background Medullary thyroid carcinoma (MTC) is a rare subtype of thyroid cancer. Other than gain‐of‐function RET mutations, no other genetic, lifestyle or environmental risk associations have been established for MTC. Several case‐control studies and meta‐analysis have examined the risk association of different SNPs with MTC in different populations but with contradictory or inconclusive results. Methods In a large cohort of 438 Indian MTC cases and 489 gender and ethnicity matched healthy controls from 1000 genome project, a comprehensive risk association of 13 SNPs of three pathways—detoxification, cell cycle regulation and RET was performed along with meta‐analysis of RET SNPs. Results Multivariate logistic regression analysis identified a protective risk association of CDKN1ASer31Arg SNP with both hereditary (OR 0.26; 95% confidence interval [CI] 0.13‐0.55; P < .001) and sporadic MTC (OR 0.53; 95% CI 0.36‐0.78; P = .001). An increased risk association was identified for NAT2Y94Y SNP (OR 1.62, 95% CI 1.17‐2.25, P = .004) and CDKN2A3′UTR SNP (OR 1.89, 95% CI 1.19‐2.98, P = .006) with sporadic MTC and RET S904S with hereditary MTC (OR 2.82, 95% CI 1.64‐4.86, P < .001). Meta‐analysis of RET SNPs including our cohort identified increased risk association of all four RET SNPs with MTC. Conclusion In this largest SNP risk association study for MTC and the only risk association study of the 13 most commonly studied MTC associated SNPs in a single cohort of this rare cancer, a significant protective risk association of CDKN1ASer31Arg SNP with MTC was shown for the first time. Meta‐analysis identified significant risk association of all four RET SNPs, not observed in previous meta‐analysis.

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Germline polymorphisms of RET and GFRA1 genes in patients with medullary thyroid carcinoma

Cited by 6 publications

References 36 publications

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

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

Genetic risk association of CDKN1A and RET gene SNPs with medullary thyroid carcinoma: Results from the largest MTC cohort and meta‐analysis

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