We have contributed to 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 it causes nonendocrine tumors (angiofibroma, collagenoma, and leiomyoma). We have identified an MEN1 variant in three large families with infrequent gastrinoma. We find germline mutations in 70-80% of probands with familial MEN1 or at lower prevalence in cases with sporadic MEN1. In contrast, probands with familial isolated hyperparathyroidism have rare (about 5%) MEN1 mutations. Among the MEN1-like families without MEN1 mutation, a rare family shows mutation of the p27 gene. p27 mutation in MEN1 is about 1% the frequency of MEN1 mutation. We have also found rare mutation of p15, p18, or p21 cyclin dependent kinase inhibitor (CDKI) genes. We will continue to explore these and other states for germline MEN1 mutations. We have also found somatic MEN1 mutation in 15 to 35% of sporadic tumors of many endocrine organs. Thus MEN1 is the gene most frequently implicated in common endocrine tumors. We will also determine the spectrum of pathologic states that the MEN1 or the CDKI genes contribute to through mutation and other mechanisms.

Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Zip Code
Simonds, William F; Varghese, Sarah; Marx, Stephen J et al. (2012) Cushing's syndrome in multiple endocrine neoplasia type 1. Clin Endocrinol (Oxf) 76:379-86
Yavuz, Sahzene; Simonds, William F; Weinstein, Lee S et al. (2012) Sleeping parathyroid tumor: rapid hyperfunction after removal of the dominant tumor. J Clin Endocrinol Metab 97:1834-41
Nilubol, Naris; Weinstein, Lee; Simonds, William F et al. (2012) Preoperative localizing studies for initial parathyroidectomy in MEN1 syndrome: is there any benefit? World J Surg 36:1368-74
Marx, Stephen J (2011) Hyperparathyroid genes: sequences reveal answers and questions. Endocr Pract 17 Suppl 3:18-27
Wang, Yan; Ozawa, Atsushi; Zaman, Shadia et al. (2011) The tumor suppressor protein menin inhibits AKT activation by regulating its cellular localization. Cancer Res 71:371-82
Agarwal, Sunita K; Mateo, Carmen M; Marx, Stephen J (2009) Rare germline mutations in cyclin-dependent kinase inhibitor genes in multiple endocrine neoplasia type 1 and related states. J Clin Endocrinol Metab 94:1826-34
Shen, H-C Jennifer; He, Mei; Powell, Anathea et al. (2009) Recapitulation of pancreatic neuroendocrine tumors in human multiple endocrine neoplasia type I syndrome via Pdx1-directed inactivation of Men1. Cancer Res 69:1858-66