title: Tuberin and hamartin expression is reduced in the majority of subependymal giant cell astrocytomas in tuberous sclerosis complex consistent with a two-hit model of pathogenesis.
abstract: Subependymal giant cell astrocytomas are distinctive brain tumors that are seen only in tuberous sclerosis complex. Although histologically benign, they cause both moribidity and occasional mortality owing to progressive growth in some patients. Tuberous sclerosis complex is an autosomal dominant genetic disorder with a high sporadic case rate that is due to mutations in either of two genes, TSC1 and TSC2, encoding hamartin and tuberin, respectively. The pathogenesis of subependymal giant cell astrocytomas in tuberous sclerosis complex is uncertain. In this study, we examined the expression of tuberin and hamartin in subependymal giant cell astrocytomas from nine patients with tuberous sclerosis complex by immunohistochemistry with confocal microscopy. Loss of hamartin expression was seen in all subependymal giant cell astrocytomas, including five from patients with germline TSC2 mutations and two from patients with germline TSC1 mutations. The subependymal giant cell astrocytomas of six of nine patients had no expression of tuberin as well, whereas three patients retained some tuberin expression. Tuberin expression was seen in one patient with a TSC2 germline mutation and two patients whose mutational status was not determined. Overall, these data indicate a loss of both tuberin and hamartin expression in the subependymal giant cell astrocytomas of patients with both TSC1 and TSC2 mutations and are consistent with a two-hit disease pathogenesis model for the development of subependymal giant cell astrocytomas.
authors.affiliation: Department of Neurology, Children's Memorial Health Institute, Warsaw, Poland. jozwiak@czd.waw.pl
authors.forename: Sergiusz
authors.initials: S
authors.lastname: Jóźwiak
authors.forename: David
authors.initials: D
authors.lastname: Kwiatkowski
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kotulska
authors.forename: Magdalena
authors.initials: M
authors.lastname: Larysz-Brysz
authors.forename: Joanna
authors.initials: J
authors.lastname: Lewin-Kowalik
authors.forename: Wiesława
authors.initials: W
authors.lastname: Grajkowska
authors.forename: Marcin
authors.initials: M
authors.lastname: Roszkowski
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology; D000912:Antibodies, Neoplasm / Q000276:immunology; D001932:Brain Neoplasms / Q000150:complications* / Q000235:genetics* / Q000276:immunology; D046508:Culture Techniques; D004252:DNA Mutational Analysis; D017353:Gene Deletion; D018315:Glioma, Subependymal / Q000150:complications* / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D020125:Mutation, Missense / Q000235:genetics; D009367:Neoplasm Staging; D017354:Point Mutation / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000235:genetics* / Q000276:immunology; D012097:Repressor Proteins / Q000235:genetics* / Q000276:immunology; D014402:Tuberous Sclerosis / Q000150:complications*; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins
chemical_list: D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D011506:Proteins; D012097:Repressor Proteins; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins