Genetic Testing in Medullary Thyroid Carcinoma
Medullary thyroid carcinoma (MTC) is rare; it occurs either sporadically or as a familial cancer. The familial syndromes that include medullary thyroid carcinoma are MEN IIA (MTC, pheochromocytoma, hyperparathyroidism), MEN IIB (MTC, pheochromocytoma, ganglioneuromatosis, marfanoid habitus), and familial medullary thyroid cancer (MTC alone). All of these are autosomal dominant disorders related to germline mutations in the ret proto-oncogene, a receptor tyrosine kinase that maps to chromosome 10q11.2.1 It is not yet understood how the mutation in this protein leads to cancer. However, sufficient numbers of families have now been studied to validate the usefulness of genetic analysis of this gene in predicting persons at risk for particular syndromes.
Heshmati and colleagues examined 33 MEN IIA kindreds with 165 members, 13 familial MTC kindreds (at least four affected family members without evidence of pheochromocytoma and hyperparathyroidism) with 108 members, 15 kindreds with other forms of hereditary MTC (two or three affected members) with 42 members, and 33 individuals with sporadic MTC. Analysis of exons 10, 11, and 13 was performed because of evidence that one of five cysteine residues in exons 10 or 11 are frequently mutated in such families, and that exon 13 may also harbor familial mutations.
Germline mutations in exons 10 and 11 were identified in 32 of 33 (97%) MEN IIA kindreds, 10 of 13 (77%) familial MTC kindreds, and 10 of 15 (67%) "other hereditary MTC" kindreds. No mutations were found in exon 13, and none of the sporadic MTC cases harbored germline mutations. Codon 634 was the most commonly mutated site in MEN IIA kindreds (73%), and a cysteine to arginine mutation (TGC to CGC) was the most common change (58%). In familial MTC, codon 618 was the most commonly mutated site (54%), and a cysteine to serine mutation (TGC to AGC) was the most common change (57%). Within MEN IIA kindreds, it appeared that patients with codon 634 mutations had earlier clinical manifestations of disease than did patients with mutations in other codons. However, there were no apparent associations between genotype and disease aggressiveness. (Heshmati HM, et al. Mayo Clin Proc 1997;72:430-436.)
COMMENTARY
Although there is considerable controversy about genetic testing in breast cancer and colon cancerin part because the prophylactic measures are so radicalgenetic testing of families of patients with MTC makes sense, medically and, according to this report, economically. MTC is the dominant cause of death in patients with MEN IIA and familial MTC. It is readily prevented by thyroidectomy, preferably between the ages of 5 and 10. Genetic testing allows identification of persons at risk for this cancer and permits effective prophylaxis. Furthermore, characterization of the mutation identifies persons at particularly high risk of developing pheochromocytoma and hyperparathyroidism. Persons with codon 634 mutations are much more likely to develop these manifestations of MEN IIA than those with mutations at other sites.
Genetic testing is also more reliable at detecting familial MTC and MEN IIA than biochemical screening with basal calcitonin levels and pentagastrin stimulation tests.2 Genetic testing is less useful at identifying MEN IIB because new germline mutations are common in these families (50%). Thus, all patients with MTC should themselves be tested for germline ret mutations, and if found, their relatives (particularly children) should also be tested and managed accordingly. If mutations are not found, linkage analysis is required. If neither mutations nor linkage analysis suggest the presence of a mutated gene, subjects and their offspring do not require further genetic or biochemical testing. Those predicted to have inherited the predisposing gene should undergo prophylactic thyroidectomy at an early age, and those with codon 634 mutations should undergo regular surveillance for pheochromocytoma (50-67% may develop it) and hyperparathyroidism (20-40% may develop it).
References
1. Mulligan LM, et al. Nat Genet 1997;6:70-74.
2. Tsai MS, et al. J Clin Endocrinol Metab 1994;78: 1261-1264.
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