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Human Molecular Genetics, 2000, Vol. 9, No. 10 1495-1500
© 2000 Oxford University Press

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

David H. Gutmann1,+, Jessica Donahoe1, Arie Perry2, Nancy Lemke3, Karen Gorse4, Kanokwan Kittiniyom4,6, Sandra A. Rempel3, Jorge A. Gutierrez5 and Irene F. Newsham4,6

Departments of 1Neurology and 2Neuropathology, Washington University School of Medicine, Box 8111, 660 S. Euclid Avenue, St Louis, MO 63110, USA, Departments of 3Neurosurgery and 4Neuropathology, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI 48202, USA and Departments of 5Anatomy and 6Pathology, Virginia Commonwealth University, PO Box 908709, Richmond, VA 23298, USA

Meningiomas are common nervous system tumors, whose molecular pathogenesis is poorly understood. To date, the most frequent genetic alteration detected in these tumors is loss of heterozygosity (LOH) on chromosome 22q. This finding led to the identification of the neurofibromatosis 2 (NF2) tumor suppressor 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, radixin and moesin. Recently, we identified another protein 4.1 gene, DAL-1 (differentially expressed in adenocarcinoma of the lung) located on chromosome 18p11.3, which is lost in ~60% of non-small cell lung carcinomas, and exhibits growth-suppressing properties in lung cancer cell lines. Given 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 investigated the possibility that loss of expression of DAL-1 was important for meningioma development. In this report, we demonstrate DAL-1 loss in 60% of sporadic meningiomas using LOH, RT–PCR, western blot and immunohistochemistry analyses. Analogous to merlin, we show that DAL-1 loss is an early event in meningioma tumorigenesis, suggesting that these two protein 4.1 family members are critical growth regulators in the pathogenesis of meningiomas. Furthermore, our work supports the emerging notion that membrane-associated alterations 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.

+ To whom correspondence should be addressed. Tel: +1 314 362 7149; Fax: +1 314 362 9462; Email: gutmannd@neuro.wustl.edu


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