Penetrance and clinical manifestations of non-hotspot germline RET mutation, C630R, in a family with medullary thyroid carcinoma.

Abstract

Germline mutations in specific hot spot-codons of the RET proto-oncogene are associated with multiple endocrine neoplasia type 2 (MEN 2). Clinical RET gene testing has been routine for the last 10 years in some countries. In Argentina, RET testing excluding MEN 2B was always reported with a mutation at codon 634, with one exception: we described a novel mutation T > C transition at codon 630 (C630R), the family to which we extend the study in the present report. This family comprised 29 members in four generations including 6 individuals affected with medullary thyroid cancer (MTC), positive for the C630R mutation and normal adrenaline/ noradrenaline and ionized calcium/parathyroid hormone levels. Two asymptomatic mutation carriers aged 5 and 11 years underwent total thyroidectomy. The histopathologic examination showed C-cell hyperplasia and microcarcinoma foci, while preoperative basal calcitonins were normal for both. Our report emphasizes the importance of testing for non-hot spot RET mutations in apparently mutation negative MEN 2 families. Furthermore, it would appear that C630R mirrors C634R in penetrance (100% in this family) and in early age of onset of MTC, although paradoxically, no pheochromocytomas and hyperparathyroidism have developed. In addition to recommending RET testing before 5 years of age; we also can postulate that codon 630 may be the key point along the extracellular domain, important in the tissue-specific penetrance.

• Authors: R J Dourisboure, S Belli, E Domenichini, E J Podestá, C Eng, A R Solano
• Journal: Thyroid : official journal of the American Thyroid Association (Thyroid) Vol. 15 Issue 7 Pg. 668-71 (Jul 2005) ISSN: 1050-7256 [Print] United States
• PMID: 16053382 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• MAS1 protein, human
• Oncogene Proteins
• Proto-Oncogene Mas
• Proto-Oncogene Proteins c-ret
• RET protein, human
• Receptor Protein-Tyrosine Kinases

Topics

• Adult
• Age of Onset
• Carcinoma, Medullary (genetics)
• Child
• Child, Preschool
• Family Health
• Female
• Germ-Line Mutation (genetics)
• Humans
• Male
• Middle Aged
• Oncogene Proteins (genetics)
• Pedigree
• Penetrance
• Proto-Oncogene Mas
• Proto-Oncogene Proteins c-ret
• Receptor Protein-Tyrosine Kinases (genetics)
• Thyroid Neoplasms (genetics)