Loss of wild-type MEN1 gene expression in multiple endocrine neoplasia type 1-associated parathyroid adenoma

Multiple endocrine neoplasia type 1 (MEN1) is a human hereditary tumor syndrome characterized by the development of endocrine adenomas of the parathyroid, anterior pituitary, and enteropancreatic tissue. Several lines of evidence have implicated the recently identified MEN1 gene located on chromosome 11q13 as a recessive tumor suppressor gene. Here, we analyzed MEN1 wild-type gene expression in tumors from a large MEN1 kindred. A deletion of codons 227-228 (678del6) located in exon 4 was found in tumor and peripheral blood complementary DNA using a simplified single-strand conformational polymorphism (SSCP) approach well suited for clinical MEN1 mutation screening. The identified 678del6 cDNA mutation deletes a potential phosphorylation site (Tyr227) and corresponds to a germ line mutation co-segregating with disease phenotype in this MEN1 family. Loss of heterozygosity analysis by fluorescent microsatellite PCR showed an exclusive loss of the MEN1 wild-type (and retention of the mutated) allele detectable in DNA from microdissected parathyroid and pancreatic, but not in adrenal, adenomas. Our findings confirm the synergism between MEN1 gene mutations and subsequent MEN1 allelic losses in the tumorigenesis of MEN1-associated adenomas.