Genetic aspects of multiple endocrine neoplasia types 1 and 2

Multiple endocrine neoplasia (MEN) type 1 is an autosomal, dominantly inherited predisposition to develop neoplastic lesions of the parathyroid glands, the neuroendocrine pancreas-duodenum, and the anterior pituitary. The genetic defect was mapped to the centromeric part of the long arm of chromosome 11 based on studies of somatic deletions in MEN-1-associated tumors and linkage analysis in families in whom the disease is segregated. Combined family and tumor analysis has shown that tumorigenesis in MEN-1 involves loss of the wild-type chromosome, indicating that the putative MEN-1 gene is a tumor suppressor gene. Similar deletions are also seen in a proportion of sporadic parathyroid and pancreatic tumors, suggesting that tumorigenesis involves related mechanisms in both sporadic and familial cases. Based on results from linkage analysis in more than 40 MEN-1 families, predictive testing for MEN-1 using DNA polymorphisms can now be performed with high accuracy. Hence, biochemical screening programs can focus on individuals at risk to identify early signs of tumor development. MEN-2, an autosomal dominant cancer syndrome of variable expressivity, has previously been localized to chromosome 10q11.2 by positional cloning tactics. The RET protooncogene mapping to the MEN2 susceptibility locus has recently emerged as a candidate gene for MEN-2A. RET, a transmembrane receptor protein, has a large glycosylated extracellular domain containing clustered cysteine residues and calcium-binding motifs, a single hydrophobic transmembrane domain, and a cytoplasmic domain with tyrosine kinase catalytic activity. Several germline missense mutations in a codon specifying one of these highly conserved cysteine residues have been detected in patients affected with MEN-2A.(ABSTRACT TRUNCATED AT 250 WORDS)