Risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germline RET mutations located in exon 10

Karin Frank-Raue (1) , Lisa A. Rybicki (2) , Zoran Erlic (3) , Heiko Schweizer (3) , Aurelia Winter (3) , Ioana Milos (3) , Sergio Pa Toledo (4) , Rodrigo A Toledo (4) , Marcos R Tavares (5) , Maria Alevizaki (6) , Caterina Mian (7) , Heide Siggelkow (8) , Michael Hüfner (8) , Nelson Wohllk (9) , Giuseppe Opocher (10) , Šárka Dvořáková (11) , Bela Bendlova (12) , Małgorzata Czetwertynska (13) , Elżbieta Skasko (13) , Marta Barontini (14) , Gabriela Sanso (14) , Christian Vorländer (15) , Ana Luiza Maia (16) , Attila Patocs (17) , Thera P Links (18) , Jan Willem de Groot (18) , Michiel N Kerstens (18) , Gerlof D. Valk (19) , Konstanze Miehle (20) , Thomas J. Musholt (21) , Josefina Biarnes (22) , Svetozar Damjanovic (23) , Mihaela Muresan (24) , Christian Wüster (25) , Martin Fassnacht (26) , Mariola Peczkowska (27) , Christine Fauth (28) , Henriette Golcher (29) , Martin A Walter (30) , Josef Pichl (31) , Friedhelm Raue (1) , Charis Eng (32) , Hartmut Neumann (33)

1 Endocrine Practice and Molecular Laboratory
2 Department of Quantitative Health Sciences and Taussig Cancer Institute
3 Section of Preventive Medicine, Department of Nephrology
4 Endocrine Genetics Unit (LIM-25), Endocrinology, Department of Internal Medicine
5 Head and Neck Division, Department of Surgery
6 Endocrine Unit, Department of Medical Therapeutics
7 Department of Medical and Surgical Sciences
8 Department of Endocrinology
9 Endocrine Section, Hospital del Salvador
10 Familial Cancer Clinic, Veneto Institute of Oncology, IRCCS & Department of Medical and Surgical Sciences
11 Department of Molecular Endocrinology
12 Department of Nuclear Medicine and Oncological Endocrinology
13 Department of Endocrinology
14 Centro de Investigaciones Endocrinológicas
15 Department of Endocrine Surgery
16 Thyroid Section, Endocrine Divison
17 Molecular Medicine Research Group, Hungarian Academy of Sciences and 2nd Department of Medicine
18 Department of Endocrinology
19 Department of Internal Medicine
20 Department of Endocrinology
21 Endocrine Surgery, Department of General and Abdominal Surgery
22 Endocrinology Unit
23 Institute of Endocrinology, Diabetes & Metabolic Diseases, Medical School
24 Department of Endocrinology
25 Private Praxis for Endocrinology
26 Department of Medicine I
27 Department of Hypertension
28 Division of Clinical Genetics, Department of Medical Genetics, Molecular and and Clinical Pharmacology
29 Department of Surgery
30 Institute of Nuclear Medicine, University Hospital
31 St.Theresien-Hospital
32 Genomic Medicine Institute
33 Nephrology

Multiple endocrine neoplasia type 2 is characterized by germline mutations in RET. For exon 10, comprehensive molecular and corresponding phenotypic data are scarce. The International RET Exon 10 Consortium, comprising 27 centers from 15 countries, analyzed patients with RET exon 10 mutations for clinical risk profiles. Presentation, age-dependent penetrance and stage-at-presentation of medullary thyroid carcinoma (MTC), pheochromocytoma and hyperparathyroidism were studied. A total of 340 subjects from 103 families, age 2-86, were registered. There were 21 distinct single nucleotide germline mutations located in codons 609 (45 subjects), 611 (50), 618 (94), and 620 (151). MTC was present in 263 registrants, pheochromocytoma in 54 and hyperparathyroidism in 8 subjects. Of the patients with MTC, 53% were detected when asymptomatic, and amongst those with pheochromocytoma, 54%. Penetrance for MTC was 4% by age 10, 25% by 25 and 80% by 50. Codon-associated penetrance by age 50 ranged from 60% (codon 611) to 86% (620). More advanced stage and increasing risk of metastases correlated with mutation in codon position (609->620) near the juxtamembrane domain. Our data provide rigorous bases for timing of pre-morbid diagnosis and personalized treatment/prophylactic procedure decisions depending on specific RET exon 10 codons affected.

Mots clés: Life Sciences

Karin Frank-Raue, Lisa A. Rybicki, Zoran Erlic, Heiko Schweizer, Aurelia Winter, et al.. Risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germline RET mutations located in exon 10. Human Mutation, 2010, 32 (1), pp.51. ⟨10.1002/humu.21385⟩. ⟨hal-00599477⟩