RESUMO
Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant genetic disease caused by RET gene germline mutations that is characterized by medullary thyroid carcinoma (MTC) associated with other endocrine tumors. Several reports have demonstrated that the RET mutation profile may vary according to the geographical area. In this study, we collected clinical and molecular data from 554 patients with surgically confirmed MTC from 176 families with MEN2 in 18 different Brazilian centers to compare the type and prevalence of RET mutations with those from other countries. The most frequent mutations, classified by the number of families affected, occur in codon 634, exon 11 (76 families), followed by codon 918, exon 16 (34 families: 26 with M918T and 8 with M918V) and codon 804, exon 14 (22 families: 15 with V804M and 7 with V804L). When compared with other major published series from Europe, there are several similarities and some differences. While the mutations in codons C618, C620, C630, E768 and S891 present a similar prevalence, some mutations have a lower prevalence in Brazil, and others are found mainly in Brazil (G533C and M918V). These results reflect the singular proportion of European, Amerindian and African ancestries in the Brazilian mosaic genome.
RESUMO
There is a considerable interindividual variation in L-thyroxine [3,5,3',5'-tetraiodo-l-thyronine (T4)] dose required for thyrotropin (thyroid-stimulating hormone) suppression in patients with differentiated thyroid cancer. To investigate whether uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1)-mediated T4 glucuronidation in liver affects T4 dose, we genotyped 101 patients for the common UGT1A1-53(TA)n polymorphism and compared T4 doses among patients having zero (5/6 and 6/6 genotypes), one (6/7 genotype), or two (7/7 and 7/8 genotypes) copies of the low-expression (TA)7 and (TA)8 alleles. A significant trend for decreasing T4 dose with increasing number of copies of (TA)7 and (TA)8 (P=0.037) and significant difference in T4 dose across the UGT1A1-53(TA)n genotypes (P=0.048) were observed, despite considerable overlap of T4 doses among different genotypes. These results are consistent with reduced T4 glucuronidation in patients with low-expression (TA)7 and (TA)8 alleles and provide the first evidence for association between UGT1A1-53(TA)n and T4-dose requirement for thyroid-stimulating hormone suppression in a natural clinical setting.