Loss of tuberin in both subependymal giant cell astrocytomas and angiomyolipomas supports a two-hit model for the pathogenesis of tuberous sclerosis tumors

Am J Pathol. 1997 Dec;151(6):1639-47.


Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by seizures, mental retardation, and tumors of skin, brain, heart, and kidney. In this study, we focused on two of the most frequent tumors in TSC patients, renal angiomyolipomas and subependymal giant 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 tumors? We used a loss of heterozygosity approach to identify tumors from TSC2 patients. We found loss of tuberin immunostaining in the spindle 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. Chromosome 16p13 loss of heterozygosity occurred in both spindle and epithelioid 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 reactive rather than neoplastic.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Angiomyolipoma / metabolism*
  • Angiomyolipoma / pathology
  • Animals
  • Antibody Specificity
  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / pathology
  • Glioma / metabolism*
  • Glioma / pathology
  • Humans
  • Immunoenzyme Techniques
  • Kidney Neoplasms / metabolism*
  • Kidney Neoplasms / pathology
  • Models, Biological
  • Rats
  • Rats, Mutant Strains
  • Repressor Proteins / immunology
  • Repressor Proteins / metabolism*
  • Tuberous Sclerosis / etiology
  • Tuberous Sclerosis / metabolism*
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins


  • Repressor Proteins
  • TSC2 protein, human
  • Tsc2 protein, rat
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins