Maylis Lebeault1, Stéphane Pinson2,3, Marine Guillaud-Bataille3,4, Anne-Paule Gimenez-Roqueplo3,5, Alain Carrie3,6, Véronique Barbu3,7, Pascal Pigny3,8, Stéphane Bezieau3,9, Jean-Marc Rey3,10, Chantal Delvincourt3,11, Sophie Giraud2,3, Charlotte Veyrat-Durebex3,12,13, Patrick Saulnier14, Nathalie Bouzamondo3,13, Marie Chabbert12, Julien Blin15, Amira Mohamed3,16, Pauline Romanet3,16, Francoise Borson-Chazot3,17, Vincent Rohmer1,3, Anne Barlier3,16, Delphine Mirebeau-Prunier3,12,13. 1. 1 Service d'Endocrinologie, CHU Angers , Angers, France . 2. 2 Laboratoire de Génétique Moléculaire , CHU Lyon, Lyon France . 3. 3 Réseau TenGen , France . 4. 4 Département de Biologie et Pathologie Médicale, Gustave Roussy, Université de Paris-Saclay, Villejuif, France . 5. 5 Service de Génétique, Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France . 6. 6 Centre de Génétique Moléculaire Chromosomique, Assistance Publique Hôpitaux de Paris , Paris, France . 7. 7 Laboratoire Commun de Biologie et Génétique Moléculaires , HUEP, SAT, AP-HP Paris, France . 8. 8 Laboratoire de Biochimie et Oncologie Moléculaire , CHU Lille, Lille, France . 9. 9 Laboratoire de Génétique Moléculaire , CHU Nantes, Nantes, France . 10. 10 Laboratoire de Biopathologie Cellulaire et Tissulaire des Tumeurs , CHU Montpellier, Montpellier, France . 11. 11 Laboratoire de Biologie Oncologique , CHU Reims, Reims, France . 12. 12 UMR CNRS 6015-INSERMU1083, Laboratoire MITOVASC, Université d'Angers, Angers, France . 13. 13 Département de Biochimie et Génétique, CHU Angers , Angers, France . 14. 14 Cellule de Méthodologie et Biostatistiques, Délégation à la Recherche Clinique et l'Innovation-DRCI, CHU Angers , Angers, France . 15. 15 Institut National du Cancer-INCa , Paris, France . 16. 16 Aix Marseille Univ, CNRS, CRN2M, UMR 7286, and APHM La Conception Hospital, Molecular Biology Laboratory, Marseille, France . 17. 17 Hospices Civils de Lyon, Pôle IMER; Université Claude Bernard Lyon 1, HESPER EA 7425 Lyon, France .
Abstract
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.
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 RETVUS. 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.
Entities:
Keywords:
RET oncogene; genetic variants; medullary thyroid cancer (MTC); multiple endocrine neoplasia type 2 (MEN2); pheochromocytoma (PHEO)