Nationwide French Study of RET Variants Detected from 2003 to 2013 Suggests a Possible Influence of Polymorphisms as Modifiers.

Autor:	Lebeault M; 1 Service d'Endocrinologie, CHU Angers , Angers, France ., Pinson S; 2 Laboratoire de Génétique Moléculaire , CHU Lyon, Lyon France .; 3 Réseau TenGen , France ., Guillaud-Bataille M; 3 Réseau TenGen , France .; 4 Département de Biologie et Pathologie Médicale, Gustave Roussy, Université de Paris-Saclay, Villejuif, France ., Gimenez-Roqueplo AP; 3 Réseau TenGen , France .; 5 Service de Génétique, Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France ., Carrie A; 3 Réseau TenGen , France .; 6 Centre de Génétique Moléculaire Chromosomique, Assistance Publique Hôpitaux de Paris , Paris, France ., Barbu V; 3 Réseau TenGen , France .; 7 Laboratoire Commun de Biologie et Génétique Moléculaires , HUEP, SAT, AP-HP Paris, France ., Pigny P; 3 Réseau TenGen , France .; 8 Laboratoire de Biochimie et Oncologie Moléculaire , CHU Lille, Lille, France ., Bezieau S; 3 Réseau TenGen , France .; 9 Laboratoire de Génétique Moléculaire , CHU Nantes, Nantes, France ., Rey JM; 3 Réseau TenGen , France .; 10 Laboratoire de Biopathologie Cellulaire et Tissulaire des Tumeurs , CHU Montpellier, Montpellier, France ., Delvincourt C; 3 Réseau TenGen , France .; 11 Laboratoire de Biologie Oncologique , CHU Reims, Reims, France ., Giraud S; 2 Laboratoire de Génétique Moléculaire , CHU Lyon, Lyon France .; 3 Réseau TenGen , France ., Veyrat-Durebex C; 3 Réseau TenGen , France .; 12 UMR CNRS 6015-INSERMU1083, Laboratoire MITOVASC, Université d'Angers, Angers, France .; 13 Département de Biochimie et Génétique, CHU Angers , Angers, France ., Saulnier P; 14 Cellule de Méthodologie et Biostatistiques, Délégation à la Recherche Clinique et l'Innovation-DRCI, CHU Angers , Angers, France ., Bouzamondo N; 3 Réseau TenGen , France .; 13 Département de Biochimie et Génétique, CHU Angers , Angers, France ., Chabbert M; 12 UMR CNRS 6015-INSERMU1083, Laboratoire MITOVASC, Université d'Angers, Angers, France ., Blin J; 15 Institut National du Cancer-INCa , Paris, France ., Mohamed A; 3 Réseau TenGen , France .; 16 Aix Marseille Univ, CNRS, CRN2M, UMR 7286, and APHM La Conception Hospital, Molecular Biology Laboratory, Marseille, France ., Romanet P; 3 Réseau TenGen , France .; 16 Aix Marseille Univ, CNRS, CRN2M, UMR 7286, and APHM La Conception Hospital, Molecular Biology Laboratory, Marseille, France ., Borson-Chazot F; 3 Réseau TenGen , France .; 17 Hospices Civils de Lyon, Pôle IMER; Université Claude Bernard Lyon 1, HESPER EA 7425 Lyon, France ., Rohmer V; 1 Service d'Endocrinologie, CHU Angers , Angers, France .; 3 Réseau TenGen , France ., Barlier A; 3 Réseau TenGen , France .; 16 Aix Marseille Univ, CNRS, CRN2M, UMR 7286, and APHM La Conception Hospital, Molecular Biology Laboratory, Marseille, France ., Mirebeau-Prunier D; 3 Réseau TenGen , France .; 12 UMR CNRS 6015-INSERMU1083, Laboratoire MITOVASC, Université d'Angers, Angers, France .; 13 Département de Biochimie et Génétique, CHU Angers , Angers, France .
Jazyk:	angličtina
Zdroj:	Thyroid : official journal of the American Thyroid Association [Thyroid] 2017 Dec; Vol. 27 (12), pp. 1511-1522. Date of Electronic Publication: 2017 Nov 03.
DOI:	10.1089/thy.2016.0399
Abstrakt:	Background: The presence of single nucleotide polymorphisms (SNPs) in the REarranged during Transfection (RET) gene has been investigated with regard to their potential role in the development or progression of medullary thyroid cancer or pheochromocytomas (PHEO) in patients with the multiple endocrine neoplasia type 2 (MEN2) syndrome. The aim of this study was to evaluate the spectrum of RET variants in France between 2003 and 2013, and to evaluate the impact of SNPs on the MEN2 A phenotype. Methods: In this retrospective cohort study, RET variants were screened in 5109 index cases, and RET pathogenic variants were screened in 2214 relatives. Exons 5, 8, 10, 11, 13, 14, 15, and 16 were characterized by Sanger sequencing. RET pathogenic variants, RET variants with unknown functional significance (VUS), and four RET SNP variants-G691S (rs1799939), L769L (rs1800861), S836S (rs1800862), and S904S (rs1800863)-were characterized and are reported in index cases. In silico analysis and classification following the recommendation of the American College of Medical Genetics and Genomics was performed for RET VUS. Each patient's age at the time of diagnosis, sex, and the endocrine neoplasias present at molecular diagnosis were recorded. Results: Twenty-six single VUS in RET without any well-defined risk profiles were found in 33 patients. Nine of these were considered probably pathogenic, 11 of uncertain significance, and six as probably benign. Three double pathogenic variants found in three patients were classified as pathogenic. A study of the entire cohort showed that patients carrying pathogenic variants or VUS in RET together with PHEO were diagnosed earlier than the others. The presence of the G691S SNP, or a combination of SNPs, increased the risk of developing PHEO but did not modify the date of the diagnosis. No association was found between SNPs and medullary thyroid cancer or hyperparathyroidism. Conclusions: The findings propose a classification of 15 of the 26 VUS in RET without any well-defined risk profiles and suggest that the G691S SNP, or a combination of SNPs, may be associated with the development of PHEO.
Databáze:	MEDLINE
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