Molecular pathology of the MEN1 gene

Sunita K. Agarwal, A. Lee Burns, Karen E. Sukhodolets, Patricia A. Kennedy, Victor H. Obungu, Alison B. Hickman, Michael E. Mullendore, Ira Whitten, Monica C. Skarulis, William F. Simonds, Carmen Mateo, Judy S. Crabtree, Peter C. Scacheri, Youngmi Ji, Elizabeth A. Novotny, Lisa Garrett-Beal, Jerrold M. Ward, Steven K. Libutti, H. Richard Alexander, Aniello CerratoMichael J. Parisi, Sonia Santa Anna-A, Brian Oliver, Settara C. Chandrasekharappa, Francis S. Collins, Allen M. Spiegel, Stephen J. Marx

Research output: Contribution to journalReview article

117 Scopus citations

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 sub-regions 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, NM23β, 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.

Original languageEnglish (US)
Pages (from-to)189-198
Number of pages10
JournalAnnals of the New York Academy of Sciences
Volume1014
DOIs
StatePublished - Jan 1 2004

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Keywords

  • AP1
  • Carcinoid
  • Gastrinoma
  • Hyperparathyroidism
  • Insulinoma
  • MEN1
  • Menin
  • Oncogene
  • Tumor suppressor

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

Cite this

Agarwal, S. K., Burns, A. L., Sukhodolets, K. E., Kennedy, P. A., Obungu, V. H., Hickman, A. B., Mullendore, M. E., Whitten, I., Skarulis, M. C., Simonds, W. F., Mateo, C., Crabtree, J. S., Scacheri, P. C., Ji, Y., Novotny, E. A., Garrett-Beal, L., Ward, J. M., Libutti, S. K., Alexander, H. R., ... Marx, S. J. (2004). Molecular pathology of the MEN1 gene. Annals of the New York Academy of Sciences, 1014, 189-198. https://doi.org/10.1196/annals.1294.020