Analysis of chromosome 22 loci in meningioma. Alterations in the leukemia inhibitory factor (LIF) locus.

Abstract

Meningiomas are typically benign tumors arising from arachnoidal cells at the base of the brain. Meningioma is thought to result from the loss or inactivation of a putative tumor suppressor gene located on chromosome 22. We analyzed a set of meningioma DNA specimens by Southern blot hybridization with chromosome 22-specific probes and by PCR using oligomer primers and probes specific to the leukemia inhibitory factor (LIF) gene. Southern analysis suggested that a subset of our specimens are monosomic for 22q11-qter and may have lost one entire copy of chromosome 22. The gene(s) involved in the etiology of meningioma has been localized to 22q11.2-12.3. The locus encoding LIF, a factor that affects the differentiation and proliferation of numerous cell types, has also been localized to this region, at 22q12.1-12.2. The partial overlap of these loci, coupled with the known involvement of the LIF gene product in growth and differentiation, suggested that the LIF locus may be associated with the meningioma defect. We have examined the LIF locus in meningioma specimens at the molecular level by PCR, and by DNA and RNA gel-blot hybridizations. Alterations in the structure and/or expression of the LIF locus were detected in several specimens, including the subset that were shown to be monosomic for 22q. All of our tumor specimens were shown to be undermethylated at the LIF locus relative to constitutional DNA from the same patients. Sequence analysis of LIF cDNA from a meningioma revealed the existence of a novel, alternatively spliced LIF mRNA. These results suggest that the LIF gene may be near the putative tumor suppressor locus associated with the development of this phenotype.