MULTIPLE ENDOCRINE NEOPLASIA TYPE-1 - CLINICAL AND GENETIC TOPICS

Multiple endocrine neoplasia type 1 (MEN1) consists of benign, and som etimes malignant, tumors (often multiple in a tissue) of the parathyro ids, enteropancreatic neuroendocrine system, anterior pituitary, and o ther tissues. Skin angiofibromas and skin collagenomas are common. Typ ically, MEN1 tumors begin two decades earlier than sporadic tumors. Be cause of tumor multiplicity and the tendency for postoperative tumor r ecurrence, specialized methods have been developed for preoperative an d intraoperative localization of many MEN1-associated tumors. The MEN1 gene was recently isolated by positional cloning. This strategy progr essively narrows the size of the candidate MEN1 gene interval on the c hromosome and then finds and tests many or, if needed, all genes withi n that interval. The MEN1 gene was finally identified because it was t he one gene that contained mutations in most DNAs from a test panel of MEN1 cases. It has been suggested that MEN1, like many hereditary can cer syndromes, is caused by mutation in a tumor suppressor gene that c ontributes to neoplasia when both gene copies in a tumor precursor cel l have been sequentially inactivated (''two-hit'' oncogenesis mechanis m). Germline MEN1 mutations were found in most families with MEN1 and in most cases of sporadic MEN1. In addition, the MEN1 gene was the gen e most likely to show acquired mutation in several sporadic or nonhere ditary tumors-parathyroid adenomas, gastrinomas, insulinomas, and bron chial carcinoids. Most germline or acquired MEN1 mutations predicted t runcation (and thus likely inactivation) of the encoded protein, suppo rting expectations for the ''first hit'' to a tumor suppressor gene. T esting for MEN1 germline mutation is possible in a research setting. C andidates for MEN1 mutation testing include patients with MEN1 or its phenocopies and first-degree relatives of persons with MEN1.