LOSS OF TUBERIN IN BOTH SUBEPENDYMAL GIANT-CELL ASTROCYTOMAS AND ANGIOMYOLIPOMAS SUPPORTS A 2-HIT MODEL FOR THE PATHOGENESIS OF TUBEROUS SCLEROSIS TUMORS

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder cha racterized by seizures, mental retardation, and tumors of skin, brain, heart, and kidney, In this study, we focused on two of the most frequ ent tumors in TSC patients, renal angiomyolipomas and subependymal gia nt cell astrocytomas (SEGAs), Two questions were addressed. First, is loss of tuberin, the product of the TSC2 gene, seen in both renal and central nervous system tumors from TSC patients? Second, when loss of tuberin occurs, does it affect each of the cell types seen in these tu mors? We used a loss of heterozygosity approach to identify tumors fro m TSC2 patients, We found loss of tuberin immunostaining in the spindl e and epithelioid cells but not in the giant cells of six TSC2 SEGAs, We also found loss of tuberin immunostaining in all three cell types ( smooth muscle, fat, and vessels) of six TSC2 angiomyolipomas. Chromoso me 16p13 loss of heterozygosity occurred in both spindle and epithelio id cells of a SEGA and in smooth muscle and fat but not the vessels of two angiomyolipomas, These results support a two-hit tumor suppressor model for the pathogenesis of SEGAs and angiomyolipomas. The vascular elements of angiomyolipomas and the giant cells of SEGAs may be react ive rather than neoplastic.