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Genotype-phenotype correlation of patients with multiple endocrine neoplasia type 2 in Japan
S Egawa1, H Futami, K Takasaki
1Growth Factor Division, National Cancer Center Research Institute, Tokyo, Japan.
Background:
Multiple endocrine neoplasia type 2 (MEN 2) is a hereditary syndrome characterized by medullary thyroid carcinoma (MTC), pheochromocytoma and hyperparathyroidism. MEN 2 is caused predominantly by germ-line mutations of the RET proto-oncogene. This study aimed to clarify the genotype-phenotype correlation in MEN 2 patients in Japan in order to modify the clinical management according to the genotype.
Methods:
Constitutive DNA of 64 MEN 2 patients (48 kindreds) were searched for mutations at exons 10, 11, 13, 14 and 16 of the RET proto-oncogene using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP), direct sequencing and restriction enzyme digestion. The clinical characteristics of the patients were obtained from a previous nationwide questionnaire survey.
Results:
Overall, 62 (96.9%) out of 64 patients had a germ-line point mutation at the hot spots. MTC and pheochromocytoma occurred equally in every genotype except C630S. Specific genotype had a correlation between tumor size and age at the operation for MTC or extent of MTC, i.e. C618S developed late onset type of MTC as compared with that of C634R, C634Y and M918T. Small MTC in C634R may be less aggressive than those in C634Y and M918T.
Conclusions:
DNA testing has good clinical implications for the management of patients with MEN 2 and the timing and operative procedures of thyroidectomy can be modified according to the genotype.
Insights
Genetic testing for Multiple Endocrine Neoplasia type 2 (MEN 2) reveals genotype-phenotype correlations. This allows for personalized management of medullary thyroid carcinoma (MTC) and other associated conditions based on specific RET proto-oncogene mutations.
Area of Science:
- Genetics
- Oncology
- Endocrinology
Background:
- Multiple Endocrine Neoplasia type 2 (MEN 2) is an inherited disorder.
- It is characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism.
- Germline mutations in the RET proto-oncogene are the primary cause of MEN 2.
Purpose of the Study:
- To investigate the genotype-phenotype correlation in Japanese MEN 2 patients.
- To guide clinical management strategies based on genetic findings.
Main Methods:
- Analyzed DNA from 64 MEN 2 patients (48 kindreds) for RET proto-oncogene mutations.
- Utilized PCR-SSCP, direct sequencing, and restriction enzyme digestion.
- Correlated genetic data with clinical characteristics from a nationwide survey.
Main Results:
- Identified germline mutations in 96.9% of patients.
- MTC and pheochromocytoma incidence was similar across genotypes, except C630S.
- Specific genotypes correlated with MTC tumor size, age at operation, and extent; C618S showed late-onset MTC compared to others. C634R-associated MTC may be less aggressive.
Conclusions:
- Genetic testing for MEN 2 has significant clinical utility.
- Genotype information can inform the timing and surgical approach for thyroidectomy.