Multiple endocrine neoplasia type 1 (MEN1): recent advances

Multiple endocrine neoplasia-type 1 (MEN 1), is characterized by the combination of tumours of the parathyroids, endocrine pancreas and anterior pituitary glands. Parathyroid tumours are the most common manifestation of MEN 1, occurring in over 90% of affected subjects by the age of 40 years, and often involve all four parathyroid glands (Trump et al., 1996). Thus, although sporadic primary hyperparathyroidism affects up to 0.2% of the population, its occurrence below the age of 40 years is unusual and should lead one to search for the other tumours associated with the MEN syndromes. Other complications of MEN 1 include carcinoid tumours, thyroid and adrenocortical adenomas and lipomas. Pituitary tumours are found in about 30% of MEN 1 subjects, of which 60% are prolactinomas and 20% are somatotrophinomas (Trump et al., 1996). Corbettaet al. (1997) in this issue, examine the frequency of the occurrence of MEN 1 in patients who initially present with pituitary tumours. Surprisingly, they report that 14% of patients with prolactinomas have evidence of primary hyperparathyroidism (and hence MEN 1), compared to less than 2% of patients with other types of pituitary tumour (Corbetta et al., 1997). However, some of their older prolactinoma patients may represent phenocopies, i.e. have two endocrine tumours that are diagnostic of MEN 1, but do not harbour the underlying genetic defect. The increasing prevalence of primary hyperparathyroidism with age means that a small number of older prolactinoma patients may, by chance, also have a coexistent parathyroid tumour. One would predict that such patients would be at a relatively low risk of developing further MEN 1associated tumours. Despite this caution, their paper serves to remind us that prolactinoma is the third most common tumour in MEN 1, and that we should be alert to it as an occasional presenting feature of the disorder (Corbetta e al., 1997). MEN 1 is inherited as an autosomal dominant trait, and genetic linkage analysis localized the abnormal gene to the long arm of chromosome 11 (11q13) in 1988 (Larsson et al., 1988). The additional finding of allelic deletion of marker loci on 11q13 in pancreatic, parathyroid and pituitary tumours from MEN 1 patients suggested that the MEN 1 gene was likely to act as a tumour suppressor gene (Larsson et al., 1988; Friedman et al., 1989; Thakkeret al., 1989). The ‘two hit’ model of tumour development proposes that a subject with an inherited (germline) inactivation of one copy of a tumour suppressor gene (first hit), requires a subsequent somatic mutation (second hit) to develop the tumour associated with the inherited syndrome. This contrasts to sporadic cases of the tumour, where 2 somatic mutations of a tumour suppressor gene are required before the tumour develops. Many of the inherited cancer syndromes (with the notable exception of MEN 2) are caused by abnormalities in tumour suppressor genes. Since the late 1980s, several groups have been working to isolate the MEN 1 gene using a classical positional cloning approach, and these studies have recently come to fruition. Chandrasekharappa et al. applied an ‘industrial’ scale approach to the problem, and performed direct DNA sequencing on about 200 kilobases of genomic DNA, encompassing most of the chromosomal region to which the MEN 1 gene had been mapped. Analysis of this sequence information yielded eight predicted genes, any of which might have been the MEN 1 gene. However, their demonstration of point mutations in germline DNA from 14 of 15 MEN 1 patients studied for one of these eight genes confirmed that it was responsible for the MEN 1 syndrome (Chandrasekharappa et l., 1997). This gene, which has been termedmenin, consists of 10 exons and encodes a protein of 610 amino acids (Chandrasekharappa et l., 1997). Menin has no homology to other known proteins, and is not conserved in lower eukaryotes (i.e. yeast), thus its function remains largely mysterious. Menin mRNA appears to be expressed ubiquitously in adult tissues, including pancreas, adrenal cortex, thyroid, testis and leucocyte. Mutational analysis of themenin gene has now been completed in germline DNA from a total of 60 families with familial MEN 1, and heterozygous mutations have been found in 56 of these kindreds (Agarwal et al., 1997; European Consortium, 1997). Furthermore, mutations have been found in 8 of 11 sporadic cases of MEN 1 (Agarwal et al., 1997). These mutations are most commonly either nonsense mutations or small deletions, both of which would predict a premature truncation of the menin protein, consistent with its putative role as a tumour suppressor gene. Overall, more than 90% of MEN 1 patients appear to have germline meningene mutations, and these mutations are scattered throughout the full length of the coding sequence of the gene (Agarwal et al., 1997; European Consortium, 1997). Furthermore, about 70% of families have their own unique mutation. This mutational heterogeneity may hinder the development of a rapid molecular genetic screening test for MEN 1 that could be used diagnostically in patients with an apparently isolated endocrine tumour (e.g. primary Commentary