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Genotype-Phenotype Correlations in Hereditary Medullary Thyroid Carcinoma: Oncological Features and Biochemical Properties¹

Departments of General Surgery (A.M., O.G., H.D.) and Pathology (R.H.), Martin Luther University Halle-Wittenberg, D-06097 Halle/Saale; Institute for Hormone and Fertility Research, University of Hamburg, Molecular Diagnostic Group (W.H.), D-22529 Hamburg; and Division of Endocrinology, Department of Internal Medicine I, University of Ulm (B.O.B.), D-89081 Ulm, Germany

Address all correspondence and requests for reprints to: Andreas Machens, M.D., Department of General Surgery, Martin Luther University Halle-Wittenberg, Ernst Grube Strasse 40, D-06097 Halle/Saale, Germany.

In hereditary medullary thyroid carcinoma (MTC), few genotype-phenotype correlations have been established. RET genotypes (exons 10, 11, 13, and 14) of 63 patients with hereditary MTC (from November 1994 to October 1999) were correlated with age at diagnosis, sex, the TNM system, and basal calcitonin levels. Mutations in exons 10, 11, 13, and 14 were demonstrated in 22% (14 of 63), 54% (34 of 63), 21% (13 of 63), and 3% (2 of 63). The median ages at diagnosis differed significantly (38, 27, 52, and 62 yr; P = 0.003). When grouped by cysteine codons (exons 10 and 11 vs. exons 13 and 14), this difference became even more evident (30 vs. 56 yr; P = 0.001). Apart from age at diagnosis, no other significant associations were noted. Based hereon, three MTC risk groups were devised according to genotype: a high risk group (codons 634 and 618) with the youngest ages of 3 and 7 yr at diagnosis; an intermediate risk group (codons 790, 620, and 611) with ages of 12, 34, and 42 yr; and a low risk group (codons 768 and 804) with ages of 47 and 60 yr, respectively. Age at diagnosis was unrelated to specific nucleotide and amino acid exchange within each codon.

The current data demonstrate that there is a significant genotype-phenotype correlation, allowing for a more individualized approach to the timing and extent of prophylactic surgery.

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