Genetic screening in hereditary medullary thyroid carcinoma

Summary Background: Medullary thyroid carcinoma (MTC) is sporadic in the great majority of cases but is the sine qua non of multiple endocrine neoplasia type 2 (MEN 2), an autosomal dominantly inherited cancer syndrome. Depending on the tissues affected, MEN 2 is divided into 3 subtypes. MEN 2A is characterized by the presence of MTC, pheochromocytoma and hyperparathyroidism. MEN 2B is characterized by MTC, pheochromocytoma and typical stigmata. FMTC comprises MTC as the only disease feature. Germline mutations in theRET protooncogene, which encodes a receptor tyrosine kinase, have been shown to cause all 3 subtypes of MEN 2. Methods: Analyses utilize PCR-based protocols targeted at exons 10, 11, 13, 14 and 16: target exonic sequences are amplified either for direct sequencing and/or restriction endonuclease digestion where mutations would create or cause loss of specific sites. Results: Mutations in one of codons 609, 611, 618, 620 (exon 10) and 634 (exon 11) are associated with MEN 2A while mutation in codon 916 (codon 16) causes MEN 2B. Recently mutations in codons 768 and 804 were shown to be associated with FMTC only. Conclusions: These findings have made accurate DNA-based genetic testing possible, thus targettingRET mutation positive individuals for prophylactic surgery and/or surveillance while mutation negative individuals can be reassured.