The MEN1 gene is a likely tumor suppressor gene because tumors in multiple endocrine neoplasia type 1 (MEN1) show loss of heterozygosity (LOH) about the MEN1 locus and because sporadic tumors of the same tissues also show 11q13 LOH implicating this gene through a similar mechanism. We have helped to lead an intramural NIH collaboration that has cloned the MEN1 gene. We are continuing to explore its clinical and its basic implications. We have proven that MEN1 inactivation causes nonendocrine tumors (angiofibroma, collagenoma, and leiomyoma) in MEN1. We find germline mutations in 70-80% of probands with familial MEN1 or with sporadic MEN1. Pobands with familial isolated hyperparathyroidism have not shown MEN1 mutations. We will continue to explore these and other MEN1-like states with rare germline MEN1 mutations. The definition of subgroups that are deficient of MEN1 mutation has promoted the identification of known genes (CASR, p27) and newely identified genees (HRPT2, AIP) in MEN1-like states. We have also found somatic MEN1 mutation in 15 to 35% of sporadic tumors of many endocrine organs. Its role in common tumors predicts that clarification of its molecular pathway will offer new chances for interventions in many common variety tumors. A mouse strain was engineered with MEN1 heterozygous inactivation. Loss of one allele of MEN1 caused giant hyperplasia of pancreatic islets. This is a polyclonal process without loss of menin. This is a phenotype from loss of one allele of MEN1 or haploinsufficiency. It is likely a tumor precursor stage and it has implications about islet development.
| Shen, H-C Jennifer; Rosen, Jennifer E; Yang, Lauren M et al. (2008) Parathyroid tumor development involves deregulation of homeobox genes. Endocr Relat Cancer 15:267-75 |
| Ozawa, Atsushi; Agarwal, Sunita K; Mateo, Carmen M et al. (2007) The parathyroid/pituitary variant of multiple endocrine neoplasia type 1 usually has causes other than p27Kip1 mutations. J Clin Endocrinol Metab 92:1948-51 |
| Agarwal, Sunita K; Impey, Soren; McWeeney, Shannon et al. (2007) Distribution of menin-occupied regions in chromatin specifies a broad role of menin in transcriptional regulation. Neoplasia 9:101-7 |
