Mutations and allelic deletions of the MEN1 gene are associated with a subset of sporadic endocrine pancreatic and neuroendocrine tumors and not restricted to foregut neoplasms

Endocrine pancreatic tumors (EPT) and neuroendocrine tumors (NET) occur spo radically and rarely in association with multiple endocrine neoplasia type 1 (MEN1). We analyzed the frequency of allelic deletions and mutations of t he recently identified MEN1 gene in 53 sporadic tumors including 30 EPT and 23 NET (carcinoids) of different locations and types. Allelic deletion of the MEN1 locus mas identified in 18/49 (36.7%) tumors (13/30, 43.3% in EPT and 5/19, 26.3% in NET) and mutations of the MEN1 gene mere present in 8/52 (15.3%) tumors (4/30 (13.3%) EPT and 4/22 (18.1%) NET). The somatic mutati ons mere clustered in the 5' region of the coding sequence and most frequen tly encompassed missense mutations. All tumors with mutations exhibited a l oss of the other allele and a wild-type sequence of the MEN1 gene in nontum orous DNA. In one additional patient with a NET of the lung and no clinical signs or history of MEN1, a 5178-9G-->A splice donor site mutation in intr on 4 was identified in both the tumor and blood DNA, indicating the presenc e of a thus far unknown MEN1 syndrome. In most tumor groups the frequency o f allelic deletions at 11q13 was 2 to 3 times higher than the frequency of identified MEN1 gene mutations. Some tumor types, including rare forms of E PT and NET of the duodenum and small intestine, exhibited mutations more fr equently than other types. Furthermore, somatic mutations were not restrict ed to foregut tumors but were also detectable in a midgut tumor (15.2% vers us 16.6%). Our data indicate that somatic MEN1 gene mutations contribute to a subset of sporadic EPT and NET, including midgut tumors. Because the fre quency of mutations varies significantly among the investigated tumor subgr oups and allelic deletions are 2 to 3 times more frequently observed, facto rs other than MEN1 gene inactivation, including other tumor-suppressor gene s on 11q13, may also be involved in the tumorigenesis of these neoplasms.