Survey of Somatic Mutations in Tuberous Sclerosis Complex (TSC) Hamartomas Suggests Different Genetic Mechanisms for Pathogenesis of TSC Lesions

Abstract

Tuberous sclerosis complex (TSC), an autosomal dominant disease caused by mutations in either TSC1 or TSC2, is characterized by the development of hamartomas in a variety of organs. Concordant with the tumor-suppressor model, loss of heterozygosity (LOH) is known to occur in these hamartomas at loci of both TSC1 and TSC2. LOH has been documented in renal angiomyolipomas (AMLs), but loss of the wild-type allele in cortical tubers appears to be very uncommon. Analysis of second, somatic events in tumors for which the status of both TSC1 and TSC2 is known is essential for exploration of the pathogenesis of TSC-lesion development. We analyzed 24 hamartomas from 10 patients for second-hit mutations, by several methods, including LOH, scanning of all exons of both TSC1 and TSC2, promoter methylation of TSC2, and clonality analysis. Our results document loss of the wild-type allele in six of seven AMLs, without evidence of the inactivation of the second allele in many of the other lesions, including tumors that appear to be clonally derived. Laser-capture microdissection further demonstrated loss of the second allele in all three cellular components of an AML. This study thus provides evidence that, in both TSC1 and TSC2, somatic mutations resulting in the loss of wild-type alleles may not be necessary in some tumor types-and that other mechanisms may contribute to tumorigenesis in this setting.

Heterozygosity for the tuberous sclerosis complex (TSC) gene products results in increased astrocyte numbers and decreased p27-Kip1 expression in TSC2+/− cells

“…(c) Fluid-phase endocytosis of cultured Tsc2+/7 astrocytes demonstrated no di erence in the rate of endocytosis compared to control Tsc2+/+ astrocytes. Derivative astrocytes were seeded at passage 2 in 6-well plates and the rate of¯uid-phase endocytosis determined as described in the Materials and methods section 1996; Wolf et al, 1997;Niida et al, 2001;Parry et al, 2000), suggesting that TSC gene heterozygosity, resulting in reduced hamartin or tuberin expression, might be su cient for the development of these abnormalities.…”

“…First, mutational analysis studies have suggested that some of the brain pathology in TSC may result from TSC gene heterozygosity and not bi-allelic inactivation (Henske et al, 1996;Wolf et al, 1997;Niida et al, 2001;Parry et al, 2000). Second, the Tsc1 or Tsc2 gene products in Drosophila antagonize insulin receptor signaling Potter et al, 2001;Gao and Pan, 2001).…”

Tuberous sclerosis complex: linking growth and energy signaling pathways with human disease

“…LOH in TSC1 or TSC2 has been observed in angiomyolipomas, rhabdomyomas and LAM cells (Carbonara et al, 1994;Green et al, 1994;Henske et al, 1995Henske et al, , 1996Smolarek et al, 1998). LOH has not been consistently observed in cerebral cortical tubers (Henske et al, 1996;Niida et al, 2001).…”

“…Angiomyolipomas have three distinct components: vessels, smooth muscle and fat cells. LOH at the TSC1 or TSC2 locus (Henske et al, 1995;Niida et al, 2001;Karbowniczek et al, 2003b) and hyperphosphorylation of S6 (El-Hashemite et al, 2003b;Karbowniczek et al, 2003b) have been observed in each of the three components of angiomyolipomas. This indicates that all three components arise from a common progenitor and suggests that the hamartin/tuberin complex regulates cellular differentiation.…”

Capacidade proliferativa in vitro de precursores neuro-gliais, telencefálicos e expressão dos genes 1 e 2 do Complexo da Esclerose Tuberosa (TSC1 e TSC2)

“…Knudson sobre genes supressores de tumor (Kudson, 1971), tem sido demonstrada experimentalmente em grande parte dos hamartomas no TSC, mas não amplamente em lesões do sistema nervoso central de pacientes TSC (Sepp et al, 1996;Henske et al, 1996;Arai et al, 1999;Niida et al, 2001). Isso pode se dever ao fato de, apesar de clonais, as hamártias e hamartomas do TSC serem compostos por um baixo percentual de célula duplamente mutadas, mas também por células reativas (Li et al, 2008;Crino et al, 2010).…”