From the Guidelines
MEN2 syndrome is associated with mutations in the RET proto-oncogene, specifically with pathogenic germline variants in the RET gene, which is a receptor tyrosine kinase involved in cell signaling pathways that regulate cell growth, differentiation, and survival. MEN2 (Multiple Endocrine Neoplasia type 2) is an inherited cancer syndrome that comes in several subtypes (MEN2A, MEN2B, and Familial Medullary Thyroid Carcinoma), all caused by different mutations in the same RET gene, as reported in the study by 1. These mutations cause the RET protein to be constantly activated, leading to uncontrolled cell growth and tumor formation primarily in endocrine glands. The most common manifestation is medullary thyroid carcinoma, which occurs in nearly all patients with MEN2. Other associated tumors include pheochromocytomas and parathyroid adenomas.
Some key points to consider:
- The RET gene mutations are inherited in an autosomal dominant fashion, as stated in the study by 1.
- Pathogenic germline RET variants are associated with striking genotype-phenotype correlations, with the clinical phenotype having characteristic and predictable features based on the affected codon, as reported in the study by 1.
- The risk for developing each of the three pathognomonic tumors in MEN2 is based on the codon-specific variant, with the most penetrant forms characterized by lifetime risks of >95% risk to develop MTC, 50% risk to develop PHEO, and, for those with “High” risk alleles, a 20–30% risk to develop PHPT, as stated in the study by 1.
- Genetic testing for RET mutations is essential for diagnosis and helps determine appropriate management strategies, including the timing of preventive thyroidectomy in affected individuals and screening of family members, as recommended in the study by 1.
The most recent and highest quality study, 1, provides guidance on risk-reducing surgery for individuals with cancer-predisposing germline pathogenic variants and no personal cancer history, and recommends that risk-reducing thyroidectomy should be offered to disease-free carriers of RET GPVs, with the timing of surgery dependent on the risk of the variant.
From the Research
Genetic Mutation Associated with Men2 Syndrome
- The genetic mutation associated with Men2 syndrome is a germline mutation of the RET proto-oncogene 2, 3, 4, 5, 6.
- This mutation can lead to the development of medullary thyroid carcinoma, pheochromocytoma, and primary hyperparathyroidism 2, 3, 4, 5, 6.
- The RET mutation is autosomal dominant, meaning that a single copy of the mutated gene is enough to increase the risk of developing Men2 syndrome 3, 4, 5, 6.
Subtypes of Men2 Syndrome
- There are two clinically distinct subtypes of Men2 syndrome: Men2A and Men2B 2, 3, 4, 5, 6.
- Men2A is associated with medullary thyroid carcinoma, pheochromocytoma, and primary hyperparathyroidism, while Men2B is associated with medullary thyroid carcinoma, pheochromocytoma, and other non-cancerous abnormalities such as Marfanoid habitus and ganglioneuromas of the intestines 5.
- Familial medullary thyroid cancer is now viewed as a phenotypic variant of Men2A with decreased penetrance for pheochromocytoma and primary hyperparathyroidism 6.
Genotype-Phenotype Correlation
- Specific RET mutations can suggest a predilection toward a particular phenotype and clinical course with strong genotype-phenotype correlation 4, 5.
- RET mutations are stratified into three risk levels: highest, high, and moderate risk, based on the age of onset and the penetrance of the medullary thyroid carcinoma 5.
- The decision regarding the age of prophylactic thyroidectomy is no longer based upon genotype alone but is currently driven by additional clinical data, such as serum calcitonin levels 5.