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Germline Homozygous Mutations at Codon 804 in the RET Protooncogene in Medullary Thyroid Carcinoma/Multiple Endocrine Neoplasia Type 2A Patients

Cancer Research-UK Department of Oncology, University of Cambridge (F.L., A.Ce., A.Cr. J.L., B.A.J.P.), Strangeways Research Laboratory, Cambridge CB1 8RN, United Kingdom; West Midlands Hospital (T.M.F.), Colman Hill, Halesowen B63 2AH, United Kingdom; Department of Medicine, Watford General Hospital (M.R.C.), Watford, United Kingdom; Department of Human Genetics, Molecular Pathology Program (M.R.), Centro Nacional de Investigaciones Oncologicas, Madrid, Spain; and East Anglian Medical Genetics Service Molecular Genetics Laboratory, Addenbrooke’s Hospital (J.W.), Cambridge, United Kingdom

Address all correspondence and requests for reprints to: A. Cebrian, Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, United Kingdom. E-mail: arancha{at}srl.cam.ac.uk.

The effect of mutations at codon 804 in the RET protooncogene is disputed. Some studies have suggested that the V804L mutation causes the low penetrance multiple endocrine neoplasia type 2 syndrome, with late onset and relatively indolent course, whereas others have reported that V804L and V804M have an aggressive potential. In this paper, we report three apparently unrelated medullary thyroid carcinoma cases homozygous for these mutations. To clarify the phenotypic heterogeneity associated with these mutations, we compare the clinical data and age of diagnosis among these three homozygous patients, six other heterozygous cases from the same populations, and other homozygous and heterozygous subjects reported previously. The data are consistent with a model in which codon 804 mutations have low penetrance, the developing of medullary thyroid carcinoma being associated with a second germline or somatic mutation. The activity and (in the case of somatic mutations) timing of these other genetic alterations in the RET gene may explain the wide clinical variability associated with germline mutations at codon 804.

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