Endocrine Abstracts

Introduction: Medullary thyroid carcinoma may be associated with Multiple Endocrine Neoplasia type 2 (MEN2), resulting from germline mutations in the RET proto-oncogene.

Objective: We aimed to describe the molecular epidemiology of the pathogenic variants V804M and V804L of the RET gene through genetic population structure analysis.

Materials and Methods: We investigated molecular data from patients with MEN2A caused by RET mutation at codon 804 enrolled at BRASMEN (Brazilian Consortium of MEN). Peripheral blood was collected, and DNA was extracted. Analysis of haplotypes related to the RET gene was performed using capillary electrophoresis for the identification of 4 microsatellite loci, by the variable number of short tandem repeats, that flank the RET gene. The definition of the haplotypes that carry the pathogenic variant in the RET gene was carried out using the Phase software for reconstruction, while GenePop was used to test if the studied loci are in Hardy-Weinberg equilibrium.

Results: We assessed data from 155 patients with a clinical diagnosis of MEN2A, who were divided into three groups according to the pathogenic variant that caused the MEN2A: 2 subpopulations for p.Val804Leu; c.2410G>C (n = 44, 12 families), and c.2410G>T (n = 10, 4 families) and one subpopulation for p.Val804Met: c.2410G>A (n = 101, 24 families). Individuals carrying the mutations c.2410G>C and c.2410G>T predominantly resided in the Ceará, a state in Northeast Brazil marked by European colonization. Individuals carrying the mutation c.2410G>A predominantly resided in the state of São Paulo, characterized by its multiethnic demographic structure. Our data showed that G>A (P < 0,05) and G>C (P < 0,05) subpopulations are not in Hardy-Weinberg equilibrium, while G>T (P> 0,05) is. The analysis of population genetic structure showed that the subpopulations had a high rate of endogamy (Fis=0,165), reinforcing that the preferential reproduction of individuals within these subpopulations may have amplified a founder effect that occurred in the historical past of the Brazilian population. However, the genetic distances between these subpopulations were moderate/low (Fst=0,051), suggesting that, despite the founder effect, genetic flows still occur between these subpopulations.

Conclusions: Our study suggests that three different founders may have originated the genetic diversity of patients with MEN2A and mutations at codon 804 of RET. Endogamy emerged as a phenomenon that may help to explain the differences between subpopulations of patients. More studies are warranted to unveil the molecular ancestry of mutations at the codon 804 of RET.