Novel MEN 1 gene findings in rare sporadic insulinoma—a case control study

Abstract

BackgroundInsulinomas, which are rare tumors causing hyperinsulinemic hypoglycemia are usually sporadic but may also occur in association with multiple endocrine neoplasia type 1 (MEN-1) syndrome an autosomal dominant disorder caused by MEN1 gene mutations. MEN1 encodes a nuclear protein Menin, a tumor suppressor which acts as an adapter and interacts with partner proteins involved in crucial activities like transcriptional regulation, cell division, proliferation and genome stability.This study reports on clinical findings and mutation screening in sporadic insulinoma patients.MethodsSeventeen patients diagnosed with insulinoma were recruited along with 30 healthy volunteers who acted as controls for the present study. The patients presented with symptoms of sweating, tremors, drowsiness, palpitations, loss of consciousness, abnormal behavior, seizures and weight gain. Detailed clinical and family history was collected from all the participants along with 5 ml of blood sample after taking informed consent.Genomic DNA isolated from blood was subjected to MEN1 gene amplification followed by direct sequencing. Nucleotide sequences obtained were compared with published MEN1 cDNA sequences. Prediction of functional effects of novel changes was done using various bioinformatics algorithms.ResultsMolecular analysis revealed presence of three novel exonic mutations (M561K, Q192K and Q261Q), two novel intronic variations c.445-44G → A and c.913-42G → C in introns two and six respectively and three reported exon SNPs; H433H (rs540012), D418D (rs2071313), A541T (rs2959656) and one intronic SNP (rs669976).ConclusionsThe study identified presence of novel pathogenic MEN1 mutations in sporadic cases of insulinoma. The new mutations identified were in regions involved in defective binding of menin to proteins implicated in genetic and epigenetic mechanisms. The outcome of the study extends the growing list of MEN1 pathogenic mutations even in sporadic cases providing consequential insight into phenotypic heterogeneity and in the expression of individual mutations.

Establishment of the First Well-differentiated Human Pancreatic Neuroendocrine Tumor Model

“…This mutation is listed as a known SNP (rs2959656) with a minor allele frequency between 6% and 16% in different populations. Although the SNP has been described in sporadic insulinoma, parathyroid adenoma, and hemangioblastoma (27), the pathogenic role of this variant is controversial due to the high frequency in the general population. Targeted sequence analysis of "classical" pNET-associated genes, that is, VHL, MEN1, TSC1, TSC2, DAXX, and ATRX did not reveal any further mutations, which is in line with findings from Jiao and colleagues reporting mutations in either of these genes in only 68% of patients with sporadic pancreatic NETs (26).…”

Two nonsense somatic mutations in MEN1 identified in sporadic insulinomas

“… found a novel MEN1 gene frameshift germline mutation, which was associated with malignant insulinoma. Moreover, a recent study found several novel pathogenic MEN1 mutations in sporadic cases of insulinoma . Herein, we found mutations in MEN1 on chromosome 11 in patients with insulinoma, which had a damaging role in the function of the encoded protein.…”

Genetic predictors of insulin-producing pancreatic tumor

“…Примерно в 5% случаев инсулинома ассоциирована с синдромом множественных эндокринных неоплазий 1-го типа (МЭН1) [1], обусловленным мутацией в гене MEN1 (кодирует ядерный протеин менин, который является опухолевым супрессором и взаимодействует с другими протеинами, участвующими в регуляции транскрипции, пролиферации клеток и стабильности генома [3]). Заболевание может манифестировать аденомами гипофиза и околощитовидных желез, панкреатическими нейроэндокринными опухолями, опухолями щитовидной железы, надпочечников, кишечника, карциноидами легких и других органов.…”

“…Jyotsna и соавт. [3], мутации в гене MEN1 могут быть выявлены и у пациентов со спорадическими инсулиномами. В исследование были включены 17 пациентов со спорадической (другие компоненты МЭН1 были исключены) инсулиномой (у 16 из них была диагностирована доброкачественная опухоль и у 1злокачественная) и 30 здоровых индивидуумов.…”