The significance of MEN1 mutations in Pituitary Carcinomas

Abstract

MEN1 syndrome Multiple endocrine neoplasia Type I (MEN1) syndrome is characterized by the onset of endocrine tumors, in particular parathyroid, digestive (predominantly gastrinoma) and anterior pituitary tumors. The incidence of the disease is estimated to be 0.25% worldwide and the syndrome can affect all age groups [1]. Patients can also develop, at a lesser degree, adrenal tumors, lipomas, meningiomas, facial angiofibromas and collagenomas. MEN1 syndrome belongs to a family of autosomal dominant disorders with a high degree of penetrance such that primary hyperparathyroidism is diagnosed in nearly all patient after the fifth decade of life [1]. The gene responsible for the syndrome (MEN1), known as a tumor suppressor gene, was identified for the first time in 1997 [2]. It is located on chromosome 11q13 and encodes MEN1, a 610-amino acid protein that finely regulates transcription, proliferation and gene expression within the cell [3]. However, its exact role in tumorigenesis still remains under investigation, given the many molecular partners with which MEN1 interacts within a complex network. The onset of the syndrome requires inheritance of a germline mutation of MEN1 and a somatic mutation (most of the time a deletion) in the tumor DNA, leading to loss of heterozygosity. These sequences are consistent with the definition of a tumor suppressor role for MEN1, according to the Knudson two-hit hypothesis [4]. While more than 1300 germline mutations within the whole sequence of the gene have been identified [4], no genotype–phenotype correlation is currently known. Nevertheless, the higher risk of death in MEN1-affected patients was recently found to be associated with mutation in the JunD interacting domains [5].