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A two-hit model for development of multiple endocrine neoplasia type 2B by RET mutations
T Iwashita1, H Murakami, K Kurokawa
1Department of Pathology, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
Abstract:
Multiple endocrine neoplasia (MEN) type 2B mutations have been reported at methionine 918 or alanine 883 in the tyrosine kinase domain of the RET proto-oncogene. Recently, a new combination of two germline missense mutations at valine 804 and tyrosine 806 was identified in a patient with MEN 2B-like clinical phenotypes including medullary thyroid carcinoma, mucosal neuroma, and marfanoid habitus. In this case, valine 804 and tyrosine 806 were replaced with methionine and cysteine, respectively. In the present study, biological activities of RET with these new mutations were compared with those with known MEN 2A or MEN 2B mutations. The transforming activity of RET with the V804M/Y806C mutation was about 8- to 13-fold higher than that of RET with a single V804M or Y806C mutation. Like RET with the M918T or A883F MEN 2B mutation, the transforming activity of RET with the V804M/Y806C mutation was not affected by substitution of phenylalanine for tyrosine 905 that abolished the activity of RET with the MEN 2A mutation. On the other hand, substitution of phenylalanine for tyrosines 864 and 952 drastically diminished the activity of RET with the V804M/Y806C, M918T or A883F mutation, suggesting that these three mutant proteins have similar biological properties.
Insights
New RET proto-oncogene mutations (V804M/Y806C) mimic Multiple Endocrine Neoplasia type 2B (MEN 2B) activity. These findings suggest similar biological properties among different MEN 2B-associated RET mutations.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Multiple Endocrine Neoplasia (MEN) types 2A and 2B are rare genetic disorders characterized by tumor development in endocrine glands.
- Mutations in the RET proto-oncogene are the primary cause of MEN 2 syndromes.
- Known MEN 2B mutations occur at methionine 918 (M918T) or alanine 883 (A883F) within the RET tyrosine kinase domain.
Observation:
- A novel combination of germline missense mutations, V804M and Y806C, was identified in a patient with MEN 2B-like phenotypes.
- These mutations involve valine 804 and tyrosine 806 in the RET tyrosine kinase domain.
- The patient presented with medullary thyroid carcinoma, mucosal neuroma, and marfanoid habitus.
Findings:
- The V804M/Y806C RET mutation exhibited significantly higher transforming activity (8- to 13-fold) compared to single V804M or Y806C mutations.
- Like established MEN 2B mutations (M918T, A883F), the V804M/Y806C mutation's activity was unaffected by Y905F substitution, which inactivates MEN 2A RET mutations.
- Conversely, substitutions at tyrosines 864 and 952 drastically reduced the activity of V804M/Y806C, M918T, and A883F RET mutants, indicating shared biological properties.
Implications:
- The V804M/Y806C mutation represents a new genetic driver for MEN 2B-like syndromes.
- Understanding the shared biological mechanisms of these RET mutations can inform targeted therapeutic strategies for MEN 2.
- Further research into the structural and functional consequences of these RET mutations is warranted for improved patient management.