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


METHODS
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.
Toledo
Rodrigo A
RA
Faculdade de Medicina da Universidade de São Paulo, Avenida Dr. Arnaldo, 455, 5 degrees andar, Cerqueira César, 012406-903, São Paulo, Brazil. toldo@usp.br
Wagner
Simona M
SM
Coutinho
Flavia L
FL
Lourenço
Delmar M
DM
Azevedo
Juliana A
JA
Longuini
Viviane C
VC
Reis
Mariana T A
MT
Siqueira
Sheila A C
SA
Lucon
Antonio M
AM
Tavares
Marcos R
MR
Fragoso
Maria C B V
MC
Pereira
Adelaide A
AA
Dahia
Patricia L M
PL
Mulligan
Lois M
LM
Toledo
Sergio P A
SP
D000310:Adrenal Gland Neoplasms / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D015153:Blotting, Western; D002478:Cells, Cultured; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics* / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D019683:Penetrance; D010641:Phenotype; D010673:Pheochromocytoma / Q000235:genetics* / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics* / Q000378:metabolism
D051096:Proto-Oncogene Proteins c-ret