title: Pathogenesis of tuberous sclerosis subependymal giant cell astrocytomas: biallelic inactivation of TSC1 or TSC2 leads to mTOR activation.
abstract: In the central nervous system, tuberous sclerosis complex (TSC) is characterized by a range of lesions including cortical tubers, white matter heterotopias, subependymal nodules, and subependymal giant cell astrocytomas (SEGAs). Recent studies have implicated an important role for the TSC genes TSC1 and TSC2, in a signaling pathway involving the mammalian target of rapamycin (mTOR) kinase. We performed immunohistochemical and genetic analyses on SEGAs from 7 TSC patients, 4 with mutations in TSC1, and 3 with mutations in TSC2. SEGA cells show high levels of phospho-S6K, phospho-S6, and phospho-Stat3, all proteins downstream of and indicative of mTOR activation. Such expression is not seen in histologically normal control tissue. Five of 6 SEGAs also showed evidence of biallelic mutation of TSC1 or TSC2, suggesting that SEGAs develop due to complete loss of a functional tuberin-hamartin complex. We conclude that TSC SEGAs likely arise through a two-hit mechanism of biallelic inactivation of TSC1 or TSC2, leading to activation of the mTOR kinase.
authors.affiliation: Division of Neuropathology, Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Chan
authors.forename: Hongbing
authors.initials: H
authors.lastname: Zhang
authors.forename: Penelope S
authors.initials: PS
authors.lastname: Roberts
authors.forename: Sergiusz
authors.initials: S
authors.lastname: Jozwiak
authors.forename: Grajkowska
authors.initials: G
authors.lastname: Wieslawa
authors.forename: Joanna
authors.initials: J
authors.lastname: Lewin-Kowalik
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kotulska
authors.forename: David J
authors.initials: DJ
authors.lastname: Kwiatkowski
mesh_terms: D000293:Adolescent; D000483:Alleles; D001254:Astrocytoma / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D002551:Cerebral Ventricle Neoplasms / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D020547:Lateral Ventricles; D019656:Loss of Heterozygosity; D008297:Male; D009154:Mutation; D010766:Phosphorylation; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D011506:Proteins / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D038601:Ribosomal Protein S6 / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D015534:Trans-Activators / Q000378:metabolism; D014402:Tuberous Sclerosis / Q000150:complications* / Q000235:genetics*; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins
chemical_list: D004268:DNA-Binding Proteins; D011506:Proteins; D012097:Repressor Proteins; D038601:Ribosomal Protein S6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D015534:Trans-Activators; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; C546842:MTOR protein, human; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases