IDENTIFICATION OF MEN1 GENE-MUTATIONS IN SPORADIC CARCINOID-TUMORS OFTHE LUNG

Lung carcinoids occur sporadically and rarely in association with mult iple endocrine neoplasia type 1 (MEN1). There are no well defined gene tic abnormalities known to occur in these tumors. We studied 11 sporad ic lung carcinoids for loss of heterozygosity (LOH) at the locus of th e MEN1 gene on chromosome 11q13, and for mutations of the MEN1 gene us ing dideoxy fingerprinting. Additionally, a lung carcinoid from a MEN1 patient was studied. In four of 11 (36%) sporadic tumors, both copies of the MEN1 gene were inactivated. All four tumors showed the presenc e of a MEN1 gene mutation and loss of the other allele. Observed mutat ions included a 1 bp insertion, a 1 bp deletion, a 13 bp deletion and a single nucleotide substitution affecting a donor splice site. Each m utation predicts truncation or potentially complete loss of menin. The remaining seven tumors showed neither the presence of a MEN1 gene mut ation nor 11q13 LOH. The tumor from the MEN1 patient showed LOH at chr omosome 11q13 and a complex germline MEN1 gene mutation, The data impl icate the MEN1 gene in the pathogenesis of sporadic lung carcinoids, r epresenting the first defined genetic alteration in these tumors.