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

Rodrigo A. Toledo, Simona M. Wagner, Flavia L. Coutinho, Delmar M. Lourenço, Juliana A. Azevedo, Viviane C. Longuini, Mariana T A Reis, Sheila A C Siqueira, Antonio M. Lucon, Marcos R. Tavares, Maria C B V Fragoso, Adelaide A. Pereira, Patricia L Dahia, Lois M. Mulligan, Sergio P A Toledo

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

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 × 4.5 × 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 acommonancestor. 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.

Original languageEnglish (US)
Pages (from-to)1318-1327
Number of pages10
JournalJournal of Clinical Endocrinology and Metabolism
Volume95
Issue number3
DOIs
StatePublished - Mar 2010

Fingerprint

Penetrance
Germ-Line Mutation
Pheochromocytoma
Tumors
Mutation
Weighing
Codon
Neoplasms
Genes
Multiple Endocrine Neoplasia Type 2a
Natural History
Haplotypes
Phenotype

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism

Cite this

Toledo, R. A., Wagner, S. M., Coutinho, F. L., Lourenço, D. M., Azevedo, J. A., Longuini, V. C., ... Toledo, S. P. A. (2010). High penetrance of pheochromocytoma associated with the novel C634Y/Y791F double germline mutation in the RET protooncogene. Journal of Clinical Endocrinology and Metabolism, 95(3), 1318-1327. https://doi.org/10.1210/jc.2009-1355

High penetrance of pheochromocytoma associated with the novel C634Y/Y791F double germline mutation in the RET protooncogene. / Toledo, Rodrigo A.; Wagner, Simona M.; Coutinho, Flavia L.; Lourenço, Delmar M.; Azevedo, Juliana A.; Longuini, Viviane C.; Reis, Mariana T A; Siqueira, Sheila A C; Lucon, Antonio M.; Tavares, Marcos R.; Fragoso, Maria C B V; Pereira, Adelaide A.; Dahia, Patricia L; Mulligan, Lois M.; Toledo, Sergio P A.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 95, No. 3, 03.2010, p. 1318-1327.

Research output: Contribution to journalArticle

Toledo, RA, Wagner, SM, Coutinho, FL, Lourenço, DM, Azevedo, JA, Longuini, VC, Reis, MTA, Siqueira, SAC, Lucon, AM, Tavares, MR, Fragoso, MCBV, Pereira, AA, Dahia, PL, Mulligan, LM & Toledo, SPA 2010, 'High penetrance of pheochromocytoma associated with the novel C634Y/Y791F double germline mutation in the RET protooncogene', Journal of Clinical Endocrinology and Metabolism, vol. 95, no. 3, pp. 1318-1327. https://doi.org/10.1210/jc.2009-1355
Toledo, Rodrigo A. ; Wagner, Simona M. ; Coutinho, Flavia L. ; Lourenço, Delmar M. ; Azevedo, Juliana A. ; Longuini, Viviane C. ; Reis, Mariana T A ; Siqueira, Sheila A C ; Lucon, Antonio M. ; Tavares, Marcos R. ; Fragoso, Maria C B V ; Pereira, Adelaide A. ; Dahia, Patricia L ; Mulligan, Lois M. ; Toledo, Sergio P A. / High penetrance of pheochromocytoma associated with the novel C634Y/Y791F double germline mutation in the RET protooncogene. In: Journal of Clinical Endocrinology and Metabolism. 2010 ; Vol. 95, No. 3. pp. 1318-1327.
@article{a1ce8553004148c4bfe8e99946771fc9,
title = "High penetrance of pheochromocytoma associated with the novel C634Y/Y791F double germline mutation in the RET protooncogene",
abstract = "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 × 4.5 × 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 acommonancestor. 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.",
author = "Toledo, {Rodrigo A.} and Wagner, {Simona M.} and Coutinho, {Flavia L.} and Louren{\cc}o, {Delmar M.} and Azevedo, {Juliana A.} and Longuini, {Viviane C.} and Reis, {Mariana T A} and Siqueira, {Sheila A C} and Lucon, {Antonio M.} and Tavares, {Marcos R.} and Fragoso, {Maria C B V} and Pereira, {Adelaide A.} and Dahia, {Patricia L} and Mulligan, {Lois M.} and Toledo, {Sergio P A}",
year = "2010",
month = "3",
doi = "10.1210/jc.2009-1355",
language = "English (US)",
volume = "95",
pages = "1318--1327",
journal = "Journal of Clinical Endocrinology and Metabolism",
issn = "0021-972X",
publisher = "The Endocrine Society",
number = "3",

}

TY - JOUR

T1 - High penetrance of pheochromocytoma associated with the novel C634Y/Y791F double germline mutation in the RET protooncogene

AU - Toledo, Rodrigo A.

AU - Wagner, Simona M.

AU - Coutinho, Flavia L.

AU - Lourenço, Delmar M.

AU - Azevedo, Juliana A.

AU - Longuini, Viviane C.

AU - Reis, Mariana T A

AU - Siqueira, Sheila A C

AU - Lucon, Antonio M.

AU - Tavares, Marcos R.

AU - Fragoso, Maria C B V

AU - Pereira, Adelaide A.

AU - Dahia, Patricia L

AU - Mulligan, Lois M.

AU - Toledo, Sergio P A

PY - 2010/3

Y1 - 2010/3

N2 - 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 × 4.5 × 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 acommonancestor. 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.

AB - 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 × 4.5 × 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 acommonancestor. 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.

UR - http://www.scopus.com/inward/record.url?scp=77749239884&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77749239884&partnerID=8YFLogxK

U2 - 10.1210/jc.2009-1355

DO - 10.1210/jc.2009-1355

M3 - Article

C2 - 20080836

AN - SCOPUS:77749239884

VL - 95

SP - 1318

EP - 1327

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0021-972X

IS - 3

ER -