Loss of tumor suppressor in lung cancer-1 (TSLC1) expression in meningioma correlates with increased malignancy grade and reduced patient survival

EZEQUIEL I. SURACE,ERIKS LUSIS,ERIN WINKELER, YOSHINORI MURAKAMI,BERND W. SCHEITHAUER, ARIE PERRY,AND DAVID H. GUTMANN

Toronto, Canada

Congreso; Ninth Annual Meeting of the Society for Neuro-Oncology; 2004

Society for Neuro-Oncology

Meningiomas constitute the second most common central nervous system tumor affecting adults. Compared to the glioma, relatively less is known about the molecular pathogenesis of meningiomas. Previously, we and others have shown that the two most frequent early genetic changes in meningioma tumorigenesis involve inactivation of the neurofibromatosis 2 (NF2) and 4.1B genes. Recently, 4.1B was shown to interact with the Tumor Suppressor in Lung Cancer-1 (TSLC1) protein, prompting us to examine the expression of TSLC1 in meningiomas. We developed specific anti-TSLC1 antibodies to examine TSLC1 expression in normal human leptomeninges, human meningioma cell lines, and human meningiomas of different pathological grades by Western blot and immunohistochemistry. Whereas TSLC1 was expressed in normal human leptomeninges by immunohistochemistry as well as in normal mouse brain and lung, TSLC1 expression was absent in three human malignant meningioma cell lines and in 30% of benign meningiomas by Western blot. To determine whether TSLC1 functioned as a tumor suppressor for meningioma, we re-expressed TSLC1 in TSLC1-deficient human meningioma cell lines. In keeping with its function as a meningioma negative growth regulator, restoration of TSLC1 expression resulted in significantly reduced cell proliferation. Lastly, we examined a large series of 123 meningiomas representing all malignancy grades. Loss of TSLC1 expression was frequently observed in anaplastic (grade III) meningiomas (82%) and the subset of WHO grade II meningiomas with high proliferative indices (87%). Moreover, loss of TSLC1 expression was associated with decreased overall patient survival, both in the entire cohort and in the atypical WHO grade II meningiomas, which exhibit the greatest variability in clinical behavior. Collectively, these results suggest that TSLC1 plays an important role in meningioma growth regulation and that TSLC1 loss may identify a subset of meningiomas with aggressive clinical behavior and reduced patient survival