Segregation of the V804L mutation and S836S polymorphism of exon 14 of the RET gene in an extended kindred with familial medullary thyroid cancer

Abstract

In multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid cancer (FMTC), the majority of germline mutations are restricted to specific positions in exons 10 and 11 of the RET gene. However, germline mutations may very occasionally occur in other exons, including exon 14 of the RET gene. Interestingly, an increased frequency of a rare germline sequence variant of the RET exon 14, S836S, has been detected in patients with sporadic medullary thyroid cancer (MTC), and this variant has been proposed to play a role in the genesis of MTC and, perhaps, FMTC. In this study we report the segregation of a germline V804L mutation and a germline sequence variant S836S in exon 14 of the RET gene in an extended Hungarian FMTC kindred comprising 80 individuals of four generations. Molecular analysis of the RET gene was performed by direct DNA sequencing in 23 family members, of whom 12 had the V804L mutation, three had the V804L mutation and S836S polymorphism in separate alleles, and six had the S836S polymorphism, all in heterozygous forms. Two of the family members had neither mutation nor polymorphism of the RET gene. Three of the family members who had the V804L mutation and one member who could not be tested for mutation were operated for non-metastatic MTC, while one member with MTC who had the V804L mutation refused surgery. In all patients affected with MTC, the disease developed relatively late in life and never caused death. None of the other family members carrying the V804L mutation and/or the S836S polymorphism had clinical or biochemical evidence of MTC. These observations suggest that the co-existence of the V804L mutation and S836S polymorphism in separate alleles does not seem to aggravate the relatively low-risk disease phenotype characteristic in most patients with codon 804 mutations of the RET exon 14.