Differential Involvement of Protein 4.1 Family Members DAL-1 and NF2 in Intracranial and Intraspinal Ependymomas

• Published in: Modern pathology 2002-05, Vol.15 (5), p.526-531
• Main Authors: Singh, Pratima K, Gutmann, David H, Fuller, Christine E, Newsham, Irene F, Perry, Arie
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Brain cancer; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Brain tumor; Child; Child, Preschool; Chromosomes; Cohort Studies; DAL-1; Ependymoma; Ependymoma - genetics; Ependymoma - metabolism; Ependymoma - pathology; Female; Gene Deletion; Genes; Glioma; Humans; Hybridization; Immunohistochemistry; In Situ Hybridization, Fluorescence; Infant; Laboratory Medicine; Male; Medicine; Medicine & Public Health; Membrane Proteins - biosynthesis; Membrane Proteins - genetics; Microfilament Proteins; Middle Aged; Mutation; Neurofibromin 2 - biosynthesis; Neurofibromin 2 - genetics; NF2; original-article; Pathogenesis; Pathology; Proteins; Spinal Cord Neoplasms - genetics; Spinal Cord Neoplasms - metabolism; Spinal Cord Neoplasms - pathology; Tumor suppressor gene; Tumor Suppressor Proteins - biosynthesis; Tumor Suppressor Proteins - genetics; Tumorigenesis; Tumors
• ISSN: 0893-3952; 1530-0285
• DOI: 10.1038/modpathol.3880558

Ependymomas are malignant CNS neoplasms with highly variable biologic behavior, including a generally better prognosis for intraspinal tumors. Inactivation of the NF2 gene on 22q12 and loss of its protein product, merlin, have been well documented in subsets of meningiomas and ependymomas. DAL-1, a related tumor suppressor and protein 4.1 family member on 18p11.3, has also been recently implicated in meningioma pathogenesis, though its role in ependymoma remains unknown. Therefore, we evaluated 27 ependymomas (12 intracranial and 15 spinal) using fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) to determine NF2/merlin and DAL-1/DAL-1 status at the DNA and protein levels. Demonstrable NF2 and DAL-1 gene deletions were each detected in 6 (22%) ependymomas. All 5 merlin losses by IHC occurred in spinal ependymomas (P = .047), whereas 5 (71%) DAL-1–negative cases were intracranial (P = .185). The former result is consistent with prior observations that NF2 mutations are generally limited to spinal ependymomas. In contrast to meningiomas, simultaneous merlin and DAL-1 losses were not encountered. Our findings suggest that (1) NF2 and DAL-1 losses are involved in the pathogenesis of spinal and intracranial ependymoma subsets, respectively and (2) given the number of cases with no demonstrable losses, other cellular perturbations must also be critical for tumori-genesis.