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Multiple endocrine neoplasia type 2: evaluation of the genotype-phenotype relationship
Linwah Yip1, Gilbert J Cote, Suzanne E Shapiro
1Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Hypothesis:
Multiple endocrine neoplasia type 2 (MEN 2) is caused by RET proto-oncogene mutations and has a strong penetrance for medullary thyroid carcinoma (MTC). Subtypes are defined by the presence or absence of pheochromocytomas, hyperparathyroidism, and characteristic clinical stigmas. We hypothesize that specific RET mutations correlate with the MEN 2 phenotype and aggressiveness of MTC.
Design:
Review of endocrine surgery database from 1951 through 2002.
Setting:
Tertiary referral center.
Patients:
Eighty-six patients from 47 kindreds were identified with MEN 2A, MEN 2B, or familial MTC. Patients were classified into 3 RET mutation risk groups: level 1, low risk for MTC (codons 609, 768, 790, 791, 804, and 891); level 2, intermediate risk (codons 611, 618, 620, and 634); and level 3, highest risk (codons 883 and 918).
Main Outcome Measures:
Stage of MTC at diagnosis and at last follow-up and frequency of pheochromocytomas and hyperparathyroidism.
Results:
RET analysis was complete for 71 patients from 39 kindreds. Multivariate analysis identified an increased likelihood of stage III or IV MTC at diagnosis with increasing age (odds ratio, 1.12 per year of age at thyroidectomy; 95% confidence interval, 1.07-1.17; P<.001) and increasing risk group (odds ratio, 14.23 per incremental increase in MTC risk group from 1 to 3; 95% confidence interval, 3.05-66.55; P<.001). Pheochromocytomas were found in 21 patients from 12 kindreds; 20 of 21 patients had codon 634 or 918 mutations. Hyperparathyroidism was found in 10 patients from 7 kindreds; 7 of 10 patients had codon 634 mutations.
Conclusion:
Specific RET mutations predict the phenotypic expression of disease and the MTC aggressiveness in patients with MEN 2, guiding the timing of thyroidectomy and screening for pheochromocytoma.
Insights
Specific RET mutations in MEN 2 correlate with disease presentation and medullary thyroid carcinoma (MTC) aggressiveness. This finding aids in timing thyroidectomy and pheochromocytoma screening for MEN 2 patients.
Area of Science:
- Endocrinology
- Genetics
- Oncology
Background:
- Multiple endocrine neoplasia type 2 (MEN 2) is a genetic disorder caused by RET proto-oncogene mutations.
- MEN 2 strongly predisposes individuals to medullary thyroid carcinoma (MTC) and can involve pheochromocytomas and hyperparathyroidism.
- Specific RET mutations are hypothesized to correlate with MEN 2 phenotype and MTC aggressiveness.
Purpose of the Study:
- To investigate the correlation between specific RET gene mutations and the clinical phenotype of MEN 2.
- To determine if RET mutations predict the aggressiveness of medullary thyroid carcinoma (MTC).
- To establish guidelines for surgical timing and screening based on genetic risk.
Main Methods:
- A retrospective review of an endocrine surgery database from 1951 to 2002 was conducted.
- Eighty-six patients from 47 kindreds with MEN 2A, MEN 2B, or familial MTC were analyzed.
- Patients were stratified into three RET mutation risk groups (low, intermediate, high) based on specific codon mutations.
Main Results:
- Multivariate analysis revealed that increasing age and higher RET mutation risk groups significantly increased the likelihood of advanced MTC (Stage III/IV) at diagnosis.
- Pheochromocytomas were predominantly associated with codon 634 or 918 RET mutations (20/21 patients).
- Hyperparathyroidism was observed in 10 patients, with 7 having codon 634 mutations.
Conclusions:
- Specific RET mutations are predictive of the phenotypic expression and MTC aggressiveness in MEN 2 patients.
- Identifying RET mutation status can guide the optimal timing for thyroidectomy.
- Genetic risk stratification aids in targeted screening for pheochromocytoma and hyperparathyroidism.