Endocrine Abstracts

Multiple endocrine neoplasia type 1(MEN1) is a hereditary condition caused by mutations in the MEN1 gene, which encodes menin protein. The syndrome predisposes to the development of tumors in both endocrine and non-endocrine systems. In patients with MEN1, pituitary adenomas (PA) occur in approximately 40% of all cases. If patient has MEN1 phenotype with no mutations in MEN1 gene, the condition is regarded as a phenocopy. The reason of several endocrine MEN1-associated tumors combination in these patients remains unknown. Knowing menin expression in groups and if there are any somatic mutations in PA can provide insight into the oncogenesis of PA. Formalin-fixed paraffin-embedded PA tissues were obtained after transnasal transsphenoidal adenomectomy(TTA). We have used following immunohistochemistry (IHC) markers: Pit-1;T-box;CAM5.2; EК-alpha; GH, ACTH, PRL, TSH, FSH, LH, menin(ab-Menin-ChIP Grade, Abcam, UK). MEN1 mutations were assessed either by Sanger sequencing or by NGS(NextSeq550, Illumina, USA). Automated bioinformatic analysis was carried out to search for somatic mutations(annotation with SnpEff, ANNOVAR, AlamutBatch). A total of 47 samples were included in the study; MEN1 gene somatic mutations were determined in 30 samples. Menin expression was assessed in 47 PAs: 11 genetically confirmed MEN1(gMEN1), 13 phenocopies of MEN1(phMEN1) — a combination of acromegaly and primary hyperparathyroidism, 23 – sporadic acromegaly(SAm). The distribution of PA according to the type of secretion in the gMEN group was: 5-ACTH, 1-PRL, 4-adenomas with mixed secretion (2-GH+PRL; 1-TSH+PRL; 1-ACTH+PRL) 1-silent gonadotroph adenoma. All 13 samples phMEN1 and 23 samples SAm were secreting GH. The median age at the time of TTA in gMEN1 was 33 years[16;47], in phMEN1 — 59[56;64], in SAm — 57[52;62]. The groups were similar in terms of sex(P>0.05). The results of menin staining (negative staining/positive cytoplasmic staining/positive nuclear staining): gMEN1-5/6/0; phMEN1-0/12/1; SAm-2/14/7. The phMEN1 showed significantly greater cytoplasmic expression of menin than gMEN1 (P=0.011). The gMEN1 differed from SAm: nuclear staining was not detected in any case (P=0.011). There were no statistically significant differences between the phMEN1 and SAm groups (P=0.141). Although there were no differences, in phMEN1 only one case showed weak menin nuclear expression, while in SAm 7 cases had nuclear expression. No somatic mutations of MEN1 gene in phMEN1 and SAm groups were identified. Menin expression is generally preserved in PA in phMEN1 and SAm groups, though with different pattern of nuclear and cytoplasmic expression, while its expression varies in PA in MEN1. No detection of somatic mutations in phMEN1 and SAm groups leads to investigate other responsible genes or epigenetic causes of different menin expression.