Risk Profile of the RET A883F Germline Mutation: An International Collaborative Study.
The A883F germline mutation of the rearranged during transfection (RET) proto-oncogene causes multiple endocrine neoplasia 2B. In the revised American Thyroid Association (ATA) guidelines for the management of medullary thyroid carcinoma (MTC), the A883F mutation has been reclassified from the highest to the high-risk level, although no well-defined risk profile for this mutation exists.



To create a risk profile for the A883F mutation for appropriate classification among the ATA risk levels.



Retrospective analysis.



International collaboration.



Included were 13 A883F carriers.



The intervention was thyroidectomy.



Earliest age of MTC, regional lymph node metastases, distant metastases, age-related penetrance of MTC and pheochromocytoma (PHEO), overall and disease-specific survival, and biochemical cure rate.



One and three carriers were diagnosed at age 7 to 9 years (median, 7.5 years) with a normal thyroid and C-cell hyperplasia, respectively. Nine carriers were diagnosed with MTC at age 10 to 39 years (median, 19 years). The earliest age of MTC, regional lymph node metastasis, and distant metastasis was 10, 20, and 20 years, respectively. Fifty percent penetrance of MTC and PHEO was achieved by age 19 and 34 years, respectively. Five- and 10-year survival rates (both overall and disease specific) were 88% and 88%, respectively. Biochemical cure for MTC at latest follow-up was achieved in 63% (five of eight carriers) with pertinent data.



MTC of A883F carriers seems to have a more indolent natural course compared with that of M918T carriers. Our results support the classification of the A883F mutation in the ATA high-risk level.
Department of Otorhinolaryngology Head and Neck Surgery, Odense University Hospital, DK-5000 Odense, Denmark.|Institute of Clinical Research, University of Southern Denmark, DK-5000 Odense, Denmark.
Jes Sloth
JS
Mathiesen
Division of Internal Medicine, Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
Mouhammed Amir
MA
Habra
Division of Diabetes, Endocrinology and Metabolism, Department of Molecular Medicine, Imperial College London, London W12 0NN, United Kingdom.
John Howard Duncan
JHD
Bassett
Molecular Endocrinology Laboratory, Department of Medicine, Imperial College London, London W12 0NN, United Kingdom.
Sirazum Mubin
SM
Choudhury
Department of Oncology and Metabolism and Endocrine Surgical Unit, University of Sheffield and Sheffield Teaching Hospitals National Health Service Foundation Trust, Royal Hallamshire Hospital, Sheffield S10 2JF, United Kingdom.
Sabapathy Prakash
SP
Balasubramanian
Department of Diabetes and Endocrinology, Leicester Royal Infirmary, University Hospitals of Leicester National Health Service Trust, Leicester LE1 5WW, United Kingdom.
Trevor A
TA
Howlett
Cancer Genetics Kolling Institute, Royal North Shore Hospital, University of Sydney, St. Leonards, New South Wales 2065, Australia.
Bruce G
BG
Robinson
Department of Genetics, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, F-75015 Paris, France.|INSERM, Unité Mixte de Recherche 970, Paris-Cardiovascular Research Center, F-75015 Paris, France.|Paris Descartes University, Faculty of Medicine, F-75006 Paris, France.
Anne-Paule
AP
Gimenez-Roqueplo
Department of Endocrinology, La Timone Hospital, Hôpitaux de Marseille, Aix-Marseille University, 13385 Marseille, France.
Frederic
F
Castinetti
Department of Clinical Medicine and Endocrinology, Aalborg University Hospital, DK-9000 Aalborg, Denmark.
Peter
P
Vestergaard
Endocrine Practice, Moleculargenetic Laboratory, 69120 Heidelberg, Germany.
Karin
K
Frank-Raue
D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000209:etiology / Q000235:genetics*; D000328:Adult; D018278:Carcinoma, Neuroendocrine / Q000209:etiology / Q000235:genetics* / Q000601:surgery; D002648:Child; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D018814:Multiple Endocrine Neoplasia Type 2b / Q000150:complications / Q000235:genetics*; D009154:Mutation; D019683:Penetrance; D010673:Pheochromocytoma / Q000209:etiology / Q000235:genetics*; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D012189:Retrospective Studies; D018570:Risk Assessment; D015996:Survival Rate; D013964:Thyroid Neoplasms / Q000209:etiology / Q000235:genetics* / Q000601:surgery; D013965:Thyroidectomy; D055815:Young Adult
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human