Endocrine Abstracts

Introduction

The clinical cases of insulinoma patients with well-studied hereditary syndromes due to mutations in the MEN1, VHL, TSC1, and TSC2 genes are repeatedly described in the literature. At the same time, the hereditary nature of the pathology is highly probable in young patients with primary multiple lesions without mutations in these genes. In such cases, one can assume the presence of germline mutations in genes with the described somatic mutations accompanying tumorigenesis and insulin hypersecretion.

Objectives

To search for novel germline mutations associated with insulinoma.

Methods

Based on the literature data, we have compiled a genetic panel that includes 10 genes. MEN1, VHL, TSC1, and TSC2, and candidate genes, which were reported to contain changes in the tissue of sporadic insulinoma (KRAS, YY1, CDKN2A, MLH1, ADCY1, CACNA2D2). Targeted sequencing of these genes was performed in a 38-year-old woman with insulinoma of pancreatic head (the disease manifested at the age of 26 years with hyperglycemia). The diagnosis was confirmed by results of histological and immunohistochemical studies (tumor size: 10х5х4 mm, ki67 – 4%, Grade 2). The concomitant pathology included gastric polyp, kidney cyst, autoimmune thyroiditis; heredity was burdened by diabetes mellitus.

Results

we revealed the heterozygous variant c.789+114A>G (rs536921599) of unknown significance in the ADCY1 gene (NM_021116.4) in intron 2. The ADCY1 gene encodes adenylate cyclase 1, which is not expressed by normal pancreatic tissue. This protein is regulated by the concentration of calcium and calmodulin. When the gene is mutated, sensitivity to calcium concentration is likely to be lost, which leads to overstimulation of insulin secretion (regardless of glucose level) and proliferation of pancreatic β-cells. The variant found in the patient has not been described in the literature. Germline biallelic or compound heterozygous mutations in ADCY1 are known to lead to hereditary hearing loss (autosomal recessive inheritance). The patient and her relatives have no pronounced hearing impairment. No changes were found in the rest of the genes included in the panel. We continue the monitoring of the patient.

Conclusion

we revealed the germline variant c.789+114A>G in the ADCY1 gene, which is involved in regulation of insulin secretion and pancreatic β-cells proliferation, in patient with insulinoma. The identified variant is possibly a novel genetic marker of tumor: we plan to clarify its clinical significance. Identification of genetic predictors of insulinoma will allow predicting the course of the disease and developing optimal tactics for managing the patients.