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

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• 作者：Carla Colombo (1)
  Emanuela Minna (2)
  Maria Grazia Rizzetti (2)
  Paola Romeo (2)
  Daniele Lecis (3)
  Luca Persani (4)
  Piera Mondellini (3)
  Marco A Pierotti (5)
  Angela Greco (2)
  Laura Fugazzola (6)
  Maria Grazia Borrello (2)
  
  1. Department of Clinical Sciences and Community Health ; University of Milan ; and Endocrine Unit ; Fondazione IRCCS Ca鈥?Granda ; Milan ; Italy
  2. Molecular Mechanisms Unit ; Department of Experimental Oncology and Molecular Medicine ; Fondazione IRCCS Istituto Nazionale dei Tumori ; Milan ; Italy
  3. Department of Experimental Oncology and Molecular Medicine ; Fondazione IRCCS Istituto Nazionale dei Tumori ; Milan ; Italy
  4. Department of Clinical Sciences and Community Health ; University of Milan ; and Division of Endocrine and Metabolic Diseases ; Ospedale San Luca ; IRCCS Istituto Auxologico Italiano ; Milan ; Italy
  5. Scientific Directorate ; Fondazione IRCCS Istituto Nazionale dei Tumori ; Milan ; Italy
  6. Department of Pathophysiology and Transplantation ; Endocrine Unit ; Fondazione IRCCS Ca鈥?Granda Ospedale Maggiore Policlinico ; Milan ; University of Milan ; Milan ; Italy
  
• 关键词：RET ; Medullary thyroid cancer ; G691S ; S891A ; Polymorphism
• 刊名：Orphanet Journal of Rare Diseases
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：10
• 期：1
• 全文大小：3,324 KB
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• 刊物主题：Medicine/Public Health, general; Pharmacology/Toxicology; Medicinal Chemistry;
• 出版者：BioMed Central
• ISSN：1750-1172

文摘

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.