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The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia
C Eng1, D Clayton, I Schuffenecker
1Division of Cancer Epidemiology and Control, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA 02115-6084, USA. charis_eng@macmailgw.dfci.harvard.edu
Objective:
Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant disorder. The 3 recognized subtypes include MEN 2A, characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (pheo), and hyperparathyroidism (HPT); MEN 2B, by MTC, pheo, and characteristic stigmata; and familial MTC (FMTC), by the presence of MTC only. The purpose of this study was to establish the relationship between specific mutations and the presence of certain disease features in MEN 2 which could help in clinical decision making.
Design:
Correlative survey study of 477 MEN 2 families.
Setting:
Eighteen tertiary referral centers worldwide.
Patients:
A total of 477 independent MEN 2 families.
Main Outcome Measures:
Association between the position and type of germline mutation in the RET proto-oncogene and the presence or absence of MTC, pheo, HPT, and/or other features in a family.
Results:
There is a statistically significant association between the presence of any mutation at a specific position (codon 634) and the presence of pheo and HPT. The presence of a specific mutation, CGC at codon 634, has yet to be associated with FMTC. Conversely, mutations at codons 768 and 804 are thus far seen only with FMTC, while codon 918 mutation is MEN 2B--specific. Rare families with both MEN 2 and Hirschsprung disease were found to have MEN 2-specific codon mutations. Patients with Hirschsprung disease presenting with such mutations should be monitored for the possible development of MEN 2 tumors.
Conclusions:
This consortium analysis suggests that genotype-phenotype correlations do exist and, if made reliably absolute, could prove useful in the future in clinical management with respect to screening, surveillance, and prophylaxis, as well as provide insight into the genetic effects of particular mutations.
Insights
Specific RET proto-oncogene mutations correlate with Multiple Endocrine Neoplasia type 2 (MEN 2) subtypes, aiding in clinical management. Understanding these genotype-phenotype correlations helps predict disease features and guide patient care.
Area of Science:
- Endocrinology
- Genetics
- Oncology
Background:
- Multiple Endocrine Neoplasia type 2 (MEN 2) is an autosomal dominant disorder with three subtypes: MEN 2A, MEN 2B, and familial medullary thyroid carcinoma (FMTC).
- MEN 2 subtypes are characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (pheo), hyperparathyroidism (HPT), and specific stigmata.
- The RET proto-oncogene is implicated in MEN 2 pathogenesis.
Purpose of the Study:
- To establish genotype-phenotype correlations between specific RET proto-oncogene mutations and the clinical features of MEN 2.
- To determine if specific mutation locations and types are associated with particular MEN 2 subtypes or associated conditions.
- To provide data that could aid in clinical decision-making for MEN 2 patients.
Main Methods:
- A correlative survey study involving 477 independent MEN 2 families.
- Data collected from eighteen tertiary referral centers worldwide.
- Analysis focused on the association between germline mutations in the RET proto-oncogene and the presence of MTC, pheo, HPT, and other features.
Main Results:
- Mutations at codon 634 of the RET proto-oncogene are significantly associated with pheochromocytoma and hyperparathyroidism.
- Specific mutations, such as CGC at codon 634, have not been linked to FMTC.
- Mutations at codons 768 and 804 are associated exclusively with FMTC, while codon 918 mutations are specific to MEN 2B.
- Rare families with MEN 2 and Hirschsprung disease harbored MEN 2-specific codon mutations, suggesting a need for monitoring these patients for MEN 2 tumors.
Conclusions:
- Genotype-phenotype correlations in MEN 2 are evident and can be reliably established.
- These correlations can inform clinical management strategies, including screening, surveillance, and prophylaxis.
- Understanding specific mutation effects provides insight into the genetic mechanisms underlying MEN 2.