THE MEN-1 GENE IS RARELY DOWN-REGULATED IN PITUITARY-ADENOMAS

The gene for multiple endocrine neoplasia type 1 (MEN-1) has recently been cloned and encodes a putative tumor suppressor protein named meni n. We have previously reported inactivating MEN-I gene mutations assoc iated with loss of heterozygosity (LOH) of the normal allele in tumors of patients with MEN-1 and in some sporadic pituitary tumors. These g enetic alterations, however, are noted in no more than 10% of sporadic adenomas. To investigate whether other mechanisms may result in down- regulation of menin gene expression in pituitary adenomas, we examined menin, gene expression by semiquantitative RT-PCR in 60 sporadic pitu itary adenomas. Ribonucleic acid (RNA) was extracted from surgically r esected, morphologically characterized tumors. Primers were designed t o amplify a 257-bp fragment span ning exons 4-6 of the MEN-1 gene. A p roduct of the predicted size was amplified from normal pituitary sampl es as well as from adenomas. Competitive PCR was performed with the ho usekeeping gene PGK-1 to quantitate menin gene expression. A comparabl e ratio of menin/PGK-1 messenger RNA was identified in all but three s amples; in two tumors with LOH, menin expression was weak, and in one tumor, menin messenger RNA was undetectable, associated with LOH and m utation of the other allele. Reduced expression of menin in some spora dic adenomas is consistent with a putative tumor suppressor role for t his gene product. However, lack of menin down-regulation in the majori ty of these tumors, which exhibit LOH at 11q13 in up to 20% of cases, provides compelling evidence for an additional tumor suppressor gene a t this locus, which is more commonly involved in the pathogenesis of p ituitary neoplasms.