Endocrine Abstracts

Objective: Phenotypic variability and lack of genotype-phenotype correlations still represent a major challenge in the surveillance of patients carrying germline MEN1 (Multiple Endocrine Neoplasia type 1) mutations. MEN1 associated gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are highly penetrant and show an indolent course. However, they are still the leading cause of death in MEN1 syndrome. Some single-center and national studies reported higher prevalence of GEP-NETs among patients with mutations predicted to affect the function of menin protein significantly (nonsense and frameshift mutations). In the present study we aimed to collect findings from MEN1 databases to identify genotype-phenotype correlations and compare them to our results on the Hungarian MEN1 cohort.

Design and methods: Clinical and genetic data of the Hungarian MEN1 index patients referred to our national referral center between 2001 and 2017 were collected and reviewed retrospectively. Patients carrying a frameshift, nonsense, splice site mutation or large deletion were considered as high-impact mutation carriers while missense or inframe mutation carriers were classified as low-impact mutation carriers. We collected data from those national databases, where the information published was sufficient enough for the current metaanalysis. Our data were compared to the Italian (N=362) and German (N=258) MEN1 cohorts, in particular considering GEP-NETs. Correlations between genotypes and clinical manifestations were calculated with χ² and Fisher’s exact test.

Results: The combined MEN1 database consisted of 620 patients. Patients carrying high-impact mutations predicted to affect the function of menin protein significantly, presented GEP-NETs significantly more frequently compared to those carrying low-impact mutations (260 vs. 76; P=0.008). Collecting patients carrying MEN1 mutations from the European national databases would result in a number of cases more than 2.700, and a number of GEP-NETs as high as 1.250. Unfortunately, the data quality available in these studies has not allowed us to draw further conclusions.

Conclusion: This study further confirmed findings of previous studies, revealing that GEP-NET associates with high impact MEN1 mutations, thus it may have prognostic consequences. Creating a European database of MEN1 patients could be a useful tool to find further genotype-phenotype associations and to help practitioners in everyday clinical practice.

Funding EFOP-3.6.3-VEKOP-16-2017-00009