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Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
Difference in development of medullary thyroid carcinoma among carriers of RET mutations in codons 790 and 791
Karin Frank-Raue1, Andreas Machens, Christian Scheuba
1Endocrine Practice, Molecular Laboratory, Heidelberg, Germany. karin.frankraue@raue-endokrinologie.de
Objectives:
Hereditary medullary thyroid carcinoma (MTC) is caused by germ-line mutations in the RET proto-oncogene. Our study addresses the difference in development of MTC between rare mutations in RET codons 790, 791 and 804.
Design:
We evaluated tumour stage, calcitonin levels, biochemical cure rates and associated endocrinopathies in 153 German/Austrian patients with RET 790 (n = 47), 791 (n = 56) and 804 mutations (n = 50), divided into index- and screening groups.
Results:
Age at diagnosis in index-patients did not differ significantly among the three codon groups (medians of 57, 61 and 53 years). Tumour stage at diagnosis was significantly less advanced with codon 791 (n = 22) than 790 (n = 16) and 804 (n = 16) mutations (P = 0.001). In screening patients, age at diagnosis did not differ significantly among the three groups (medians 19, 24 and 32 years). Tumour stage at diagnosis was also significantly less advanced with codon 791 (n = 34) than 790 (n = 31) and 804 (n = 34) (P = 0.032). Preoperative basal calcitonin levels were significantly lower in codon 791 carriers compared to codon 790 carriers, and cure rates were significantly higher in both index (75%vs. 31%; P = 0.03) and screening patients (100%vs. 75%; P = 0.015). Additional endocrinopathies were observed only with codon 791 carriers (four pheochromocytomas and two hyperparathyroidism).
Conclusion:
There is a significant difference in MTC development with less extensive C-cell disease, higher cure rate and more frequent additional endocrinopathies in carriers of RET codon 791 mutations compared with carriers of codons 790 and 804 mutations. This information should be considered when age of prophylactic thyroidectomy is discussed.
Insights
RET codon 791 mutations in hereditary medullary thyroid carcinoma (MTC) are linked to less advanced tumors and higher cure rates compared to RET 790 and 804 mutations. This finding impacts decisions regarding prophylactic thyroidectomy timing.
Area of Science:
- Genetics
- Oncology
- Endocrinology
Background:
- Hereditary medullary thyroid carcinoma (MTC) arises from germ-line mutations in the RET proto-oncogene.
- Specific RET mutations, particularly in codons 790, 791, and 804, influence MTC development and clinical presentation.
Purpose of the Study:
- To compare the clinical differences in MTC development among patients with rare RET mutations in codons 790, 791, and 804.
- To inform clinical management strategies, including prophylactic thyroidectomy, based on specific RET mutation profiles.
Main Methods:
- Evaluation of tumor stage, calcitonin levels, biochemical cure rates, and associated endocrinopathies.
- Analysis of 153 German/Austrian patients with RET 790 (n=47), 791 (n=56), and 804 (n=50) mutations, stratified into index and screening groups.
Main Results:
- RET codon 791 mutations were associated with significantly less advanced tumor stage at diagnosis in both index and screening patient groups.
- Patients with RET codon 791 mutations exhibited significantly lower preoperative calcitonin levels and higher cure rates compared to those with RET codon 790 mutations.
- Additional endocrinopathies, including pheochromocytoma and hyperparathyroidism, were exclusively observed in carriers of RET codon 791 mutations.
Conclusions:
- RET codon 791 mutations are associated with a distinct MTC phenotype characterized by less extensive C-cell disease and improved treatment outcomes.
- The presence of additional endocrinopathies in RET codon 791 carriers warrants careful monitoring and management.
- These findings underscore the importance of considering specific RET mutation types when determining the optimal age for prophylactic thyroidectomy in at-risk individuals.
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