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Relevance of RET proto-oncogene mutations in sporadic medullary thyroid carcinoma
N Wohllk1, G J Cote, M M Bugalho
1Section of Endocrinology, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Abstract:
Analysis of peripheral blood or tumor DNA samples from 101 patients with apparent sporadic medullary thyroid carcinoma (MTC) was performed to assess the frequency of RET proto-oncogene mutations in this patient population. Peripheral blood and/or tumor DNA was amplified by polymerase chain reaction. DNA sequence or restriction enzyme analysis was performed to detect mutations of RET proto-oncogene codons 609, 611, 618, 620, 634, 768, and 918. Six of 101 patients with apparent sporadic MTC had peripheral blood DNA mutations more commonly associated with hereditary MTC. In 4 patients, these mutations led to the identification of previously unrecognized kindreds. The remaining 2 patients were examples of de novo mutations. A codon 918 mutation was found in 14 of 57 (approximately 25%) tumor DNA samples. Mutations were not identified in the remaining patients. In this large cancer center population, approximately 6% of patients with sporadic MTC carry peripheral blood DNA mutations, either inherited or de novo, more commonly associated with MEN 2A or familial MTC. Seven additional gene carriers were identified as a direct result of these studies, a 2-fold multiplying effect. We conclude routine application of RET proto-oncogene testing should be included in all cases of apparent sporadic MTC.
Insights
Genetic testing for RET proto-oncogene mutations in patients with sporadic medullary thyroid carcinoma (MTC) can identify hereditary forms. Routine testing is recommended to detect these mutations and uncover previously unknown familial cases.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Medullary thyroid carcinoma (MTC) can be sporadic or hereditary.
- RET proto-oncogene mutations are linked to hereditary MTC syndromes like MEN 2A and familial MTC.
- Identifying RET mutations in sporadic MTC cases can reveal underlying hereditary predispositions.
Purpose of the Study:
- To determine the frequency of RET proto-oncogene mutations in patients with apparent sporadic medullary thyroid carcinoma.
- To assess the clinical utility of RET mutation screening in sporadic MTC.
- To identify potential hereditary MTC kindreds within the sporadic MTC patient cohort.
Main Methods:
- Analysis of peripheral blood and tumor DNA from 101 patients with apparent sporadic MTC.
- Polymerase chain reaction (PCR) amplification of DNA.
- DNA sequencing or restriction enzyme analysis to detect RET proto-oncogene mutations at specific codons (609, 611, 618, 620, 634, 768, 918).
Main Results:
- Six of 101 patients (approx. 6%) with apparent sporadic MTC harbored peripheral blood RET mutations associated with hereditary MTC.
- These mutations identified 4 new kindreds and 2 de novo mutations.
- A codon 918 mutation was detected in 14 of 57 tumor DNA samples (approx. 25%).
Conclusions:
- Approximately 6% of sporadic MTC patients carry detectable RET mutations in peripheral blood, indicating hereditary forms.
- Routine RET proto-oncogene testing should be incorporated into the management of all sporadic MTC cases.
- This approach facilitates the identification of additional gene carriers and potential hereditary MTC families.