title: Apparent preferential loss of heterozygosity at TSC2 over TSC1 chromosomal region in tuberous sclerosis hamartomas.
abstract: To investigate the molecular mechanisms of tuberous sclerosis (TSC) histopathologic lesions, we have tested for loss of heterozygosity the two TSC loci (TSC1 and TSC2) and seven tumor suppressor gene-containing regions (TP53, NF1, NF2, BRCA1, APC, VHL, and MLM) in 20 hamartomas from 18 TSC patients. Overall, eight angiomyolipomas, eight giant cell astrocytomas, one cortical tuber, and three rhabdomyomas were analyzed. Loss of heterozygosity at either TSC locus was found in a large fraction of the informative patients, both sporadic (7/14) and familial (1/4). Interestingly, a statistically significant preponderance of loss of heterozygosity at TSC2 was observed in the sporadic group (P < 0.01). Among the possible explanations considered, the bias in the selection for TSC patients with the most severe organ impairment seems particularly appealing. According to this view, a TSC2 defect might confer a greater risk for early kidney failure or, possibly, a more rapid growth of a giant cell astrocytoma. None of the seven antioncogenes tested showed loss of heterozygosity, indicating that the loss of either TSC gene product may be sufficient to promote hamartomatous cell growth. Finally, the observation of loss of heterozygosity at different markers in an astrocytoma and in an angiomyolipoma from the same patient might suggest the multifocal origin of the second-hit mutation.
authors.affiliation: Dipartimento di Genetica, Biologia e Chimica Medica, Università di Torino, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Carbonara
authors.forename: L
authors.initials: L
authors.lastname: Longa
authors.forename: E
authors.initials: E
authors.lastname: Grosso
authors.forename: G
authors.initials: G
authors.lastname: Mazzucco
authors.forename: C
authors.initials: C
authors.lastname: Borrone
authors.forename: M L
authors.initials: ML
authors.lastname: Garrè
authors.forename: M
authors.initials: M
authors.lastname: Brisigotti
authors.forename: G
authors.initials: G
authors.lastname: Filippi
authors.forename: A
authors.initials: A
authors.lastname: Scabar
authors.forename: A
authors.initials: A
authors.lastname: Giannotti
authors.forename: P
authors.initials: P
authors.lastname: Falzoni
authors.forename: G
authors.initials: G
authors.lastname: Monga
authors.forename: G
authors.initials: G
authors.lastname: Garini
authors.forename: M
authors.initials: M
authors.lastname: Gabrielli
authors.forename: P
authors.initials: P
authors.lastname: Riegler
authors.forename: C
authors.initials: C
authors.lastname: Danesino
authors.forename: M
authors.initials: M
authors.lastname: Ruggieri
authors.forename: G
authors.initials: G
authors.lastname: Magro
authors.forename: N
authors.initials: N
authors.lastname: Migone
mesh_terms: D002872:Chromosome Deletion; D016147:Genes, Tumor Suppressor; D006222:Hamartoma / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D011110:Polymorphism, Genetic; D012097:Repressor Proteins / Q000235:genetics*; D014402:Tuberous Sclerosis / Q000235:genetics*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins
chemical_list: D012097:Repressor Proteins; C000624653:TSC2 protein, human; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins