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Age-Related Progression to Hereditary Medullary Thyroid Cancer is Associated with Gene Mutations

The findings of a European multi-centre study show a significant age-related progression from C-cell hyperplasia to medullary thyroid carcinoma and nodal metastasis among patients with rearranged during transfection (RET) mutations with the codon 634 genotype.

"Among the patients with the codon 634 genotype malignant transformation was present as early as 1 year of age," writes Andreas Machens, MD, Martin-Luther-Universitat Halle-Wittenberg, Germany and colleagues. They add that the cumulative age-related risk of medullary thyroid carcinoma increased progressively with age.

Investigators of the European Multiple Endocrine Neoplasia (EUROMEN) study enrolled 207 patients with evidence of a RET point mutation in the germ line who had undergone total thyroidectomy after genetic confirmation of the RET point mutation. Patients were 20 years old or younger and were clinically asymptomatic. The 207 participants (98 male, 109 female) belonged to 145 families and of these 29 had the familial medullary thyroid carcinoma phenotype and 112 had the MEN-2A phenotype. The remaining 4 families had spontaneous MEN-2B mutations.

Overall histologic findings in the thyroid revealed 5.3% of the patients had normal architecture, 31.9% had C-cell hyperplasia, 59.4% had medullary thyroid carcinomas without nodal metastases, and 3.4% had medullary thyroid carcinoma with nodal metastases.

Among the 207 patients, mutated RET codon 618 was found in 9.2%; codons 620 and 790 in 6.8% each; codon 891 in 2.9%; codon 791 in 2.4%; codons 609, 611, 804, and 918 in 1.9% each; codon 768 in 1.0%; and codon 630 in 0.5% of the patients. Mutated RET codon 634 was evident in 62.3% of the 207 patients making this the only subgroup with adequate numbers for the purposes of statistical analysis. Among this subgroup of patients progression of C-Cell hyperplasia occurred at the mean age of 6.9 years, progression of node-negative medullary thyroid carcinoma occurred at a mean age of 10.1 years, and progression of node-positive medullary thyroid carcinoma occurred at a mean age of 16.7 years. The investigators note that the age-related penetrance was unaffected by the type of amino acid substitution encoded by the various codon 634 mutations.

"The codon-specific differences in the age at presentation of cancer and the familial rates of concomitant adrenal and parathyroid involvement suggest that the risk of progression was based on the transforming potential of the individual RET mutation," Dr. Machens and colleagues write. They conclude, "these data provide initial guidelines for the timing of prophylactic thyroidectomy in asymptomatic carriers of RET gene mutations."

N Engl J Med 2003;349:1517-25.

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