Endocrine Abstracts

Background: Although it is well-known that single pathogenic variants in the gene MEN1 are responsible for the development of multiple endocrine neoplasia type 1 (MEN1), the outcome of the disease in individual patients cannot be deduced from known genetic factors, the clinical picture of other family members, nor environmental data. Encouraged by publications suggesting a possible role of the genetic background in MEN1 outcome, we performed a study that aimed at searching for pathways or biological processes in which genetic variants are identified, that might clarify the different phenotypes in MEN1 patients.

Matherials and methods: The exomes of MEN1 patients with confirmed pathogenic genetic variants in MEN1 were sequenced on an Illumna HiSeq platform. The results served for two analyses: (1) lack or presence of pancreatic tumour, and (2) insulinoma or non-insulinoma pancreatic tumour. For each analysis, three patient pairs were available. Genetic analyses were based on genes with nonsynonymous exonic, splice-site, 5’UTR and 3’UTR variants identified in patients with the given clinical phenotype under investigation. The identified genes were interpreted for their function, gene ontology annotations, interactions, and pathways.

Results: (1) The genes identified in MEN1 patients with vs those without pancreatic tumours were annotated primarily to be involved in metabolic processes, cellular component organization or biogenesis, and biological regulation. Annotations of the individual genes included pancreas development, enteroendocrine cell differentiation, cellular detoxification, lipid metabolic process, and vitamin metabolic process. After adding interactions, the most significantly enriched pathways were BMP signalling and regulation and TGF-beta signalling pathway. (2) In insulinoma- vs non-insulinoma-patients, biological process annotations primarily indicated genes involved in metabolic processes and cellular response to stimulus. Individual gene annotations included lipid metabolic process, response to chemical, regulation of hormone levels, insulin signalling, and secretion. Together with close interaction partners, the following pathways were enriched, among others: metabolism of lipids; oxidation by cytochrome P450; synthesis of IP2, IP, and Ins in the cytosol; transcription factor regulation in adipogenesis; vitamin D receptor pathway; cytoplasmic ribosomal proteins; and selenoamino acid metabolism.

Conclusions: Although the genetic background of MEN1 is well established, we identified inherited genetic variations that differed depending on the clinical outcomes and seemed to be logically linked to the analysed symptoms. Our results give a better insight in the different clinical presentation of MEN1 patients. Analyses on other MEN1 characteristics are currently under investigation.

The project has been funded by the National Science Centre, Poland, grant no. 2015/17/N/NZ5/00129