Molecular Pathology of the MEN1 Gene

Abstract

Multiple endocrine neoplasia type 1 (MEN1), among all syndromes, causes tumors in the highest number of tissue types. Most of the tumors are hormone producing (e.g., parathyroid, enteropancreatic endocrine, anterior pituitary) but some are not (e.g., angiofibroma). MEN1 tumors are multiple for organ type, for regions of a discontinuous organ, and for subregions of a continuous organ. Cancer contributes to late mortality; there is no effective prevention or cure for MEN1 cancers. Morbidities are more frequent from benign than malignant tumor, and both are indicators for screening. Onset age is usually earlier in a tumor type of MEN1 than of nonhereditary cases. Broad trends contrast with those in nonneoplastic excess of hormones (e.g., persistent hyperinsulinemic hypoglycemia of infancy). Most germline or somatic mutations in the MEN1 gene predict truncation or absence of encoded menin. Similarly, 11q13 loss of heterozygosity in tumors predicts inactivation of the other MEN1 copy. MEN1 somatic mutation is prevalent in nonhereditary, MEN1-like tumor types. Compiled germline and somatic mutations show almost no genotype/phenotype relation. Normal menin is 67 kDa, widespread, and mainly nuclear. It may partner with junD, NF-kB, PEM, SMAD3, RPA2, FANCD2, NM23beta, nonmuscle myosin heavy chain II-A, GFAP, and/or vimentin. These partners have not clarified menin's pathways in normal or tumor tissues. Animal models have opened approaches to menin pathways. Local overexpression of menin in Drosophila reveals its interaction with the jun-kinase pathway. The Men1+/- mouse has robust MEN1; its most important difference from human MEN1 is marked hyperplasia of pancreatic islets, a tumor precursor stage.

Menin regulates pancreatic islet growth by promoting histone methylation and expression of genes encoding p27 Kip1 and p18 INK4c

“…2 A), but, by 18 weeks and later, we observed further reductions of islet Men1 mRNA, coinciding with the loss of detectable nuclear menin in ␤ cells. These islet pheno- types mimic those reported in patients with MEN1 syndrome and in Men1 ϩ/Ϫ mice that developed insulin-producing tumors after loss of the other Men1 allele (3,5,7,(27)(28)(29). Thus, this in vivo model provided an opportunity to elucidate the basis for islet tumor formation after loss of menin expression.…”

“…Menin localizes to the nucleus and regulates gene transcription (7). Recent biochemical studies demonstrate that menin associates with a nuclear protein complex that includes the trithorax group (TrxG) members MLL, MLL2, and Ash2 (8)(9)(10).…”

The clinical, pathological, and genetic features of familial isolated pituitary adenomas

“…MEN1 syndrome, an autosomal dominant disease caused by mutations in the MEN1 gene on chromosome 11q13 that encodes the regulatory protein menin, is characterized by the presence of typical patterns of endocrine active and inactive tumors and non-endocrine tumors (6). In patients with mutations in the MEN1 gene, pituitary adenomas occur in w40% of cases (7).…”

Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors

“…Tumor development is associated with deletion or mutation of the remaining MEN1 allele (1,2). MEN1 mutations have also been reported in a variety of sporadic endocrine tumors including those commonly seen in multiple endocrine neoplasia syndrome type 1 (MEN1) as well as gastric and pulmonary carcinoid tumors (3). Men1 knockout mice have provided many insights into the role of menin in endocrine homeostasis and tumor suppression (4)(5)(6)(7).…”