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This Article Accepted manuscript (PDF) All Versions of this Article: ERC-08-0105v1 15/4/1035    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Milos, I. Articles by Neumann, H. Search for Related Content PubMed PubMed Citation Articles by Milos, I. Articles by Neumann, H.

I Milos, Nephrology, University of Freiburg Medical Centre, Freiburg, Germany
K Frank-Raue, Endocrinology, Private Praxis for Endocrinology, Heidelberg, Germany
N Wohllk, Endocrine Section, Hospital del Salvador, Universidad de Chile, Santiago de Chile, Chile
A Maia, Thyroid Section Endocrine Divison, Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
E Pusiol, Institutos de Histologia, Embriologia y Patologia Tiroidea, Universidad Nacional de Cuyo, Mendoza, Argentina
A Patocs, Molecular Medicine Research Group, Hungarian Academy of Sciences and 2nd Department of Medicine, Semmelweis University, Budapest, Hungary
M Robledo, Hereditary Endocrine Cancer Group, Spanish National Cancer Center, Madrid and ISCIII Center for Biomedical Research on Rare Diseases, Madrid, Spain
J Biarnes, Endocrinology Unit, Hospital Dr Josep Trueta de Girona, Girona, Spain
M Barontini, Centro de Investigaciones Endocrinologicas, Hospital de Ninos R. Gutierrez, Buenos Aires, Argentina
T Links, Department of Endocrinology, University Medical Center Groningen, Groningen, Netherlands
J de Groot, Department of Endocrinology, University Medical Center Groningen, Groningen, Netherlands
S Dvorakova, Department of Molecular Endocrinology, Institute of Endocrinology, Prague, Czech Republic
M Peczkowska, Institute of Cardiology, Warsaw, Poland
L Rybicki, Department of Quantitative Health Sciences, Lerner Research Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, United States
M Sullivan, Nephrology, University of Freiburg Medical Centre, Freiburg, Germany
F Raue, Private Praxis for Endocrinology, Heidelberg, Germany
I Zosin, Department of Endocrinology, University of Medicine and Pharmacy Victor Babes, Timisoara, Romania
C Eng, Genomic Medicine Institute, Cleveland Clinic Foundation, Cleveland, United States
H Neumann, Nephrology, University of Freiburg Medical Centre, Freiburg, Germany

Correspondence: Hartmut Neumann, Email: hartmut.neumann{at}uniklinik-freiburg.de

Abstract

RET testing in multiple endocrine neoplasia type 2 for molecular diagnosis is the paradigm for the practice of clinical cancer genetics. However, precise data for distinct mutation-based risk profiles are not available. Here, we survey the clinical profile for one specific genotype as a model, TGC to TGG in codon 634 (C634W). By international efforts, we ascertained all available carriers of the RET C634W mutation. Age-at-diagnosis, penetrance, and clinical complications were analyzed for medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism (HPT), as well as overall survival. Our series comprises 92 carriers from 20 unrelated families worldwide. Sixty-eight subjects had MTC diagnosed at age 3-72 years (mean 29). Lymph node metastases were observed in 16 subjects aged 20-72 and distant metastases in 4 subjects aged 28-69. Forty-one subjects had pheochromocytoma detected at age 18-67 (mean 36). Amongst the 28 subjects with MTC and pheochromocytoma, 6 developed pheochromocytoma before MTC. Six subjects had HPT diagnosed at age 26-52 (mean 39). Eighteen subjects died; of the 16 with known causes of death, 8 died of pheochromocytoma and 4 of MTC. Penetrance for MTC is 52% by age 30 and 83% by age 50; for pheochromocytoma penetrance is 20% by age 30 and 67% by age 50, and for HPT penetrance is 3% by age 30 and 21% by age 50. These data provide, for the first time, RET C634W-specific neoplastic risk and age-related penetrance profiles. The data may facilitate risk assessment and genetic counseling.