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Orphanet Journal of Rare Diseases
Published in: Orphanet Journal of Rare Diseases 1/2015

Open Access 01-12-2015 | Research

The modifier role of RET-G691S polymorphism in hereditary medullary thyroid carcinoma: functional characterization and expression/penetrance studies

Authors: Carla Colombo, Emanuela Minna, Maria Grazia Rizzetti, Paola Romeo, Daniele Lecis, Luca Persani, Piera Mondellini, Marco A Pierotti, Angela Greco, Laura Fugazzola, Maria Grazia Borrello

Published in: Orphanet Journal of Rare Diseases | Issue 1/2015

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Abstract

Background

Hereditary medullary thyroid carcinoma (MTC) is caused by germ-line gain of function mutations in the RET proto-oncogene, and a phenotypic variability among carriers of the same mutation has been reported. We recently observed this phenomenon in a large familial MTC (FMTC) family carrying the RET-S891A mutation. Among genetic modifiers affecting RET-driven MTC, a role has been hypothesized for RET-G691S non-synonymous polymorphism, though the issue remains controversial. Aim of this study was to define the in vitro contribution of RET-G691S to the oncogenic potential of the RET-S891A, previously shown to harbour low transforming activity.

Methods

The RET-S891A and RET-G691S/S891A mutants were generated by site-directed mutagenesis, transiently transfected in HEK293T cells and stably expressed in NIH3T3 cells. Their oncogenic potential was defined by assessing the migration ability by wound healing assay and the anchorage-independent growth by soft agar assay in NIH3T3 cells stably expressing either the single or the double mutants. Two RET-S891A families were characterised for the presence of RET-G691S.

Results

The functional studies demonstrated that RET-G691S/S891A double mutant displays a higher oncogenic potential than RET-S891A single mutant, assessed by focus formation and migration ability. Moreover, among the 25 RET-S891A carriers, a trend towards an earlier age of diagnosis was found in the MTC patients harboring RET-S891A in association with RET-G691S.

Conclusions

We demonstrate that the RET-G691S non-synonymous polymorphism enhances in vitro the oncogenic activity of RET-S891A. Moreover, an effect on the phenotype was observed in the RET-G691S/S891A patients, thus suggesting that the analysis of this polymorphism could contribute to the decision on the more appropriate clinical and follow-up management.
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Literature
1.
Arighi E, Borrello MG, Sariola H. RET tyrosine kinase signaling in development and cancer. Cytokine Growth Factor Rev. 2005;16(4–5):441–67.CrossRefPubMed
2.
Cebrian A, Lesueur F, Martin S, Leyland J, Ahmed S, Luccarini C, et al. Polymorphisms in the initiators of RET (rearranged during transfection) signaling pathway and susceptibility to sporadic medullary thyroid carcinoma. J Clin Endocrinol Metab. 2005;90(11):6268–74.CrossRefPubMed
3.
Baumgartner-Parzer SM, Lang R, Wagner L, Heinze G, Niederle B, Kaserer K, et al. Polymorphisms in exon 13 and intron 14 of the RET protooncogene: genetic modifiers of medullary thyroid carcinoma? J Clin Endocrinol Metab. 2005;90:6232–6.CrossRefPubMed
4.
Machens A, Frank-Raue K, Lorenz K, Rondot S, Raue F, Dralle H. Clinical relevance of RET variants G691S, L769L, S836S and S904S to sporadic medullary thyroid cancer. Clin Endocrinol (Oxf). 2012;76(5):691–7.CrossRef
5.
Fugazzola L, Muzza M, Mian C, Cordella D, Barollo S, Alberti L, et al. RET genotypes in sporadic medullary thyroid cancer: studies in a large Italian series. Clin Endocrinol (Oxf). 2008;69(3):418–25.CrossRef
6.
Margraf RL, Crockett DK, Krautscheid PM, Seamons R, Calderon FR, Wittwer CT, et al. Multiple endocrine neoplasia type 2 RET protooncogene database: repository of MEN2-associated RET sequence variation and reference for genotype/phenotype correlations. Hum Mutat. 2009;30(4):548–56.CrossRefPubMed
7.
Robledo M, Gil L, Pollan M, Cebrian A, Ruiz S, Azanedo M, et al. Polymorphisms G691S/S904S of RET as genetic modifiers of MEN 2A. Cancer Res. 2003;63:1814–7.PubMed
8.
Elisei R, Cosci B, Romei C, Bottici V, Sculli M, Lari R, et al. RET exon 11 (G691S) polymorphism is significantly more frequent in sporadic medullary thyroid carcinoma than in the general population. J Clin Endocrinol Metab. 2004;89:3579–84.CrossRefPubMed
9.
Cardot-Bauters C, Leteurtre E, Leclerc L, Vantyghem MC, Do CC, Wemeau JL, et al. Does the RET variant G691S influence the features of sporadic medullary thyroid carcinoma? Clin Endocrinol (Oxf). 2008;69(3):506–10.CrossRef
10.
Gil L, Azanedo M, Pollan M, Cristobal E, Arribas B, Garcia-Albert L, et al. Genetic analysis of RET, GFR alpha 1 and GDNF genes in Spanish families with multiple endocrine neoplasia type 2A. Int J Cancer. 2002;99:299–304.CrossRefPubMed
11.
Costa P, Domingues R, Sobrinho LG, Bugalho MJ. RET polymorphisms and sporadic medullary thyroid carcinoma in a Portuguese population. Endocrine. 2005;27(3):239–43.CrossRefPubMed
12.
Figlioli G, Landi S, Romei C, Elisei R, Gemignani F. Medullary thyroid carcinoma (MTC) and RET proto-oncogene: mutation spectrum in the familial cases and a meta-analysis of studies on the sporadic form. Mutat Res. 2013;752(1):36–44.CrossRefPubMed
13.
Lantieri F, Caroli F, Ceccherini I, Griseri P. The involvement of the RET variant G691S in medullary thyroid carcinoma: conflicting results of meta-analyses need to be reconciled. Int J Cancer. 2013;133(7):1760–1.CrossRefPubMed
14.
Lesueur F, Cebrian A, Robledo M, Niccoli-Sire P, Svensson KA, Pinson S, et al. Polymorphisms in RET and its coreceptors and ligands as genetic modifiers of multiple endocrine neoplasia type 2A. Cancer Res. 2006;66(2):1177–80.CrossRefPubMed
15.
Sawai H, Okada Y, Kazanjian K, Kim J, Hasan S, Hines OJ, et al. The G691S RET polymorphism increases glial cell line-derived neurotrophic factor-induced pancreatic cancer cell invasion by amplifying mitogen-activated protein kinase signaling. Cancer Res. 2005;65(24):11536–44.CrossRefPubMed
16.
Narita N, Tanemura A, Murali R, Scolyer RA, Huang S, Arigami T, et al. Functional RET G691S polymorphism in cutaneous malignant melanoma. Oncogene. 2009;28(34):3058–68.CrossRefPubMedCentralPubMed
17.
Borrello MG, Aiello A, Peissel B, Rizzetti MG, Mondellini P, Degl’Innocenti D, et al. Functional characterization of the MTC-associated germline RET-K666E mutation: evidence of oncogenic potential enhanced by the G691S polymorphism. Endocr Relat Cancer. 2011;18(4):519–27.CrossRefPubMed
18.
Vandenbosch K, Renard M, Uyttebroeck A, Sciot R, Matthijs G, Legius E. Medullary thyroid carcinoma in a child with a new RET mutation and a RET polymorphism. Genet Couns. 2005;16(1):95–100.PubMed
19.
Schulte KM, Machens A, Fugazzola L. McGregor A, az-Cano S, Izatt L, Aylwin S, Talat N, Beck-Peccoz P, Dralle H: The clinical spectrum of multiple endocrine neoplasia type 2a caused by the rare intracellular RET mutation S891A. J Clin Endocrinol Metab. 2010;95(9):E92–7.CrossRefPubMed
20.
Plaza MI, Koster R, van der Sloot AM, Quax WJ, Osinga J, Van Der ST, et al. RET-familial medullary thyroid carcinoma mutants Y791F and S891A activate a Src/JAK/STAT3 pathway, independent of glial cell line-derived neurotrophic factor. Cancer Res. 2005;65(5):1729–37.CrossRef
21.
Iwashita T, Kato M, Murakami H, Asai N, Ishiguro Y, Ito S, et al. Biological and biochemical properties of Ret with kinase domain mutations identified in multiple endocrine neoplasia type 2B and familial medullary thyroid carcinoma. Oncogene. 1999;18:3919–22.CrossRefPubMed
22.
Romei C, Mariotti S, Fugazzola L, Taccaliti A, Pacini F, Opocher G, et al. Multiple endocrine neoplasia type 2 syndromes (MEN 2): results from the ItaMEN network analysis on the prevalence of different genotypes and phenotypes. Eur J Endocrinol. 2010;163(2):301–8.CrossRefPubMed
23.
Fugazzola L, Cerutti N, Mannavola D, Ghilardi G, Alberti L, Romoli R, et al. Multigenerational familial medullary thyroid cancer (FMTC): evidence for FMTC phenocopies and association with papillary thyroid cancer. Clin Endocrinol (Oxf). 2002;56(1):53–63.CrossRef
24.
Bongarzone I, Pierotti MA, Monzini N, Mondellini P, Manenti G, Donghi R, et al. High frequency of activation of tyrosine kinase oncogenes in human papillary thyroid carcinoma. Oncogene. 1989;4:1457–62.PubMed
25.
Giacchè M, Panarotto A, Tosini R, Mori L, Orsini A, Cherubini L, et al. Evidence of a founder effect in thirteen families with medullary thyroid cancer carrying RET Ser891Ala mutation. [Abstract PP346] XXXIII National Congress of the Italian Society of Endocrinology. J Endocr Invest. 2009;32(2 Suppl):193.
26.
Compton CC, Byrd DR, Garcia-Aguilar J, Kurup P, Kurtzman SH, Olawaiye A, et al. TNM classification of malignat tumors. In: AJCC Cancer Staging Handbook. 7th ed. New York: Springer Verlag; 2012.CrossRef
27.
Pacini F, Schlumberger M, Dralle H, Elisei R, Smit JW, Wiersinga W. European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium. Eur J Endocrinol. 2006;154(6):787–803.CrossRefPubMed
28.
Kloos RT, Eng C, Evans DB, Francis GL, Gagel RF, Gharib H, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009;19(6):565–612.CrossRefPubMed
29.
Hofstra RM, Fattoruso O, Quadro L, Wu Y, Libroia A, Verga U, et al. A novel point mutation in the intracellular domain of the ret protooncogene in a family with medullary thyroid carcinoma. J Clin Endocrinol Metab. 1997;82:4176–8.PubMed
30.
Hibi Y, Ohye T, Ogawa K, Shimizu Y, Shibata M, Kagawa C, et al. Pheochromocytoma as the first manifestation of MEN2A with RET mutation S891A: report of a case. Surg Today. 2014;44(11):2195–200.CrossRefPubMedCentralPubMed
31.
Lesueur F, Cebrian A, Cranston A, Leyland J, Faid TM, Clements MR, et al. Germline homozygous mutations at codon 804 in the RET protooncogene in medullary thyroid carcinoma/multiple endocrine neoplasia type 2A patients. J Clin Endocrinol Metab. 2005;90(6):3454–7.CrossRefPubMed
32.
Bongarzone I, Vigano’ E, Alberti L, Borrello MG, Pasini B, Greco A, et al. Full activation of MEN2B mutant RET by an additional MEN2A mutation or by ligand (GDNF) stimulation. Oncogene. 1998;16:2295–301.CrossRefPubMed
Metadata
Title
The modifier role of RET-G691S polymorphism in hereditary medullary thyroid carcinoma: functional characterization and expression/penetrance studies
Authors
Carla Colombo
Emanuela Minna
Maria Grazia Rizzetti
Paola Romeo
Daniele Lecis
Luca Persani
Piera Mondellini
Marco A Pierotti
Angela Greco
Laura Fugazzola
Maria Grazia Borrello
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Orphanet Journal of Rare Diseases / Issue 1/2015
Electronic ISSN: 1750-1172
DOI
https://doi.org/10.1186/s13023-015-0231-z

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