Loss of DAL-1, a protein 4.1-related tumor suppressor, is an important early event in the pathogenesis of meningiomas

Meningiomas are common nervous system tumors, whose molecular pathogenesis is poorly understood. To date, the most frequent genetic alteration detecte d in these tumors is loss of heterozygosity (LOH) on chromosome 22q. This f inding led to the identification of the neurofibromatosis 2 (NF2) tumor sup pressor gene on 22q12, which is inactivated in 40% of sporadic meningiomas. The NF2 gene product, merlin (or schwannomin), is a member of the protein 4.1 family of membrane-associated proteins, which also includes ezrin, radi xin and moesin. Recently, we identified another protein 4.1 gene, DAL-1 (di fferentially expressed in adenocarcinoma of the lung) located on chromosome 18p11.3, which is lost in similar to 60% of non-small cell lung carcinomas , and exhibits growth-suppressing properties in lung cancer cell lines. Giv en the homology between DAL-1 and NF2 and the identification of significant LOH in the region of DAL-1 in lung, breast and brain tumors, we investigat ed the possibility that loss of expression of DAL-1 was important for menin gioma development. In this report, we demonstrate DAL-1 loss in 60% of spor adic meningiomas using LOH, RT-PCR, western blot and immunohistochemistry a nalyses. Analogous to merlin, we show that DAL-1 loss is an early event in meningioma tumorigenesis, suggesting that these two protein 4.1 family memb ers are critical growth regulators in the pathogenesis of meningiomas. Furt hermore, our work supports the emerging notion that membrane-associated alt erations are important in the early stages of neoplastic transformation and the study of such alterations may elucidate the mechanism of tumorigenesis shared by other tumor types.