A long-sought needle in the haystack: the multiple endocrine neoplasia type 1 gene.

The recent identification of the gene underlying the pathogenesis of multiple endocrine neoplasia type 1 (MEN1) by Chandrasekharappa et al. is a significant advancement and will help to elucidate mechanisms of tumorigenesis in endocrine glands and provides more accurate tools to identify gene carriers at an early stage (1). MEN1 is an autosomal dominant cancer syndrome predominantly characterized by tumors of the parathyroid glands (in 90 to 100% of cases), the anterior pituitary (in ,50 to 65% of cases) and the neuroendocrine pancreas (in ,30 to 75% of cases) (2). In addition, many other tumors occur at increased frequency in MEN1 patients. This impressive list includes, among others, thyroid adenomas, follicular thyroid carcinomas, adrenocortical tumors, carcinoids in various locations, lipomas, angiofibromas, angiomyolipomas, and pinealomas. Besides the development of mass effects, these neoplasias may lead to altered secretion of hormones such as parathyroid hormone, prolactin, growth hormone, adrenocorticotropin, insulin, glucagon, gastrin and a multitude of other biologically active peptides (e.g. chromogranins, pancreatic polypeptide, vasoactive intestinal peptide, somatostatin, calcitonin), resulting in the respective clinical pictures. The association of four enlarged parathyroid glands and an eosinophilic pituitary adenoma was recognized at the beginning of the century by Erdheim (3), and Wermer proposed in 1954 an autosomal dominant defect with high penetrance based on the observation of a family in which the father and four of nine children presented with at least two of the classical MEN1 tumors (4). Zollinger-Ellison syndrome, gastrinomas causing hyperacidity, multiple and recurrent peptic ulcers and diarrhea, was described in 1955 (5). Although the prevalence of MEN1 is probably underestimated because of lack of recognition, it is estimated to range between 1 in 10 000 and 1 in 100 000. By age 50, the penetrance reaches almost 100% for parathyroid tumors which form the most common manifestation of the syndrome. What is the underlying genetic mechanism? Based on studies of sporadic and hereditary retinoblastomas, Knudson formulated the ‘two-hit model’ in 1971 (6). According to this concept, a tumor can develop when both copies of the retinoblastoma gene become defective in a retinal cell, either through two somatic events (sporadic retinoblastoma) or through somatic loss of the normal allele in an individual with an hereditary defect in the other allele (hereditary retinoblastoma). Cloning of the retinoblastoma gene subsequently confirmed the validity of this model. Analogous to the ‘two-hit model’ established in retinoblastomas, it was hypothesized that an early step of tumorigenesis in MEN1 involves loss of a tumor suppressor gene. The defective allele is inherited in a Mendelian fashion and present in the germline, the second hit consists in the loss of the wild-type allele as a somatic event in the affected tissue. The mode of inheritance thus follows a dominant pattern, but the tumorigenesis results from a recessive loss of the tumor suppressor gene in a given organ.