20080836

pubmed:Citation

3

Context: Previous studies have shown that double RET mutations may be associated with unusual multiple endocrine neoplasia type 2 (MEN 2) phenotypes. Objective: Our objective was to report the clinical features of patients harboring a previously unreported double mutation of the RET gene and to characterize this mutation in vitro. Patients: Sixteen patients from four unrelated families and harboring the C634Y/Y791F double RET germline mutation were included in the study. Results: Large pheochromocytomas measuring 6.0-14 cm and weighing up to 640 g were identified in the four index cases. Three of the four tumors were bilateral. High penetrance of pheochromocytoma was also seen in the C634Y/Y791F-mutation-positive relatives (seven of nine, 77.7%). Of these, two cases had bilateral tumors, one presented with multifocal tumors, two cases had large tumors (>5 cm), and one case, which was diagnosed with a large (5.5 x 4.5 x 4.0 cm) pheochromocytoma, reported early onset of symptoms of the disease (14 yr old). The overall penetrance of pheochromocytoma was 84.6% (11 of 13). Development of medullary thyroid carcinoma in our patients seemed similar to that observed in patients with codon 634 mutations. Haplotype analysis demonstrated that the mutation did not arise from a common ancestor. In vitro studies showed the double C634Y/Y791F RET receptor was significantly more phosphorylated than either activated wild-type receptor or single C634Y and Y791F RET mutants. Conclusions: Our data suggest that the natural history of the novel C634Y/Y791F double mutation carries a codon 634-like pattern of medullary thyroid carcinoma development, is associated with increased susceptibility to unusually large bilateral pheochromocytomas, and is likely more biologically active than each individual mutation.

eng

AIM

MEDLINE

1945-7197

Electronic

NLM

1318-27

pubmed-meshheading:20080836-Adrenal Gland Neoplasms, pubmed-meshheading:20080836-Adult, pubmed-meshheading:20080836-Blotting, Western, pubmed-meshheading:20080836-Cells, Cultured, pubmed-meshheading:20080836-Female, pubmed-meshheading:20080836-Genetic Association Studies, pubmed-meshheading:20080836-Genetic Predisposition to Disease, pubmed-meshheading:20080836-Genetic Testing, pubmed-meshheading:20080836-Haplotypes, pubmed-meshheading:20080836-Humans, pubmed-meshheading:20080836-Middle Aged, pubmed-meshheading:20080836-Multiple Endocrine Neoplasia Type 2a, pubmed-meshheading:20080836-Mutation, pubmed-meshheading:20080836-Pedigree, pubmed-meshheading:20080836-Penetrance, pubmed-meshheading:20080836-Phenotype, pubmed-meshheading:20080836-Pheochromocytoma, pubmed-meshheading:20080836-Proto-Oncogene Proteins c-ret

High penetrance of pheochromocytoma associated with the novel C634Y/Y791F double germline mutation in the RET protooncogene.

Journal Article, Research Support, Non-U.S. Gov't