ALTERATIONS IN THE RAP1 SIGNALING PATHWAY ARE COMMON IN HUMAN GLIOMAS

Several inherited predisposition to cancer syndromes are associated wi th the development of nervous system tumors. Tuberous sclerosis comple x (TSC) is an autosomal dominant disorder in which affected individual s are at risk for developing astrocytomas. One of the genes responsibl e for this disorder is TSC2, located on chromosome 16p, and encoding a 180 kDa protein (tuberin) that functions in part as a negative regula tor of rap1. Previous studies from our laboratory demonstrated that 30 % of sporadic astrocytomas have reduced or absent tuberin expression, In addition to loss of tuberin in sporadic astrocytomas, aberrant rap1 mediated signaling may also result from overexpression of rap1. In th is study, we test the hypothesis that alterations in the rap1 signalin g pathway are frequently observed in certain subsets of gliomas compar ed to other tumors of the nervous system. Analysis of sporadic astrocy tomas and ependymomas demonstrated either increased rap1 or reduced/ab sent tuberin protein expression in 50-60% of different cohorts of thes e gliomas, compared to 30-33% of sporadic schwannomas and meningiomas and none of eight oligodendrocyte tumors. These results suggest that a lterations in the rap1 signaling pathway are important in the developm ent of certain sporadic human gliomas.