Table of Contents
CancerMail from the National Cancer Institute
UI - 21375671
AU - Niida Y; Stemmer-Rachamimov AO; Logrip M; Tapon D; Perez R; Kwiatkowski DJ; Sims K; MacCollin M; Louis DN; Ramesh V
TI - Survey of somatic mutations in tuberous sclerosis complex (TSC) hamartomas suggests different genetic mechanisms for pathogenesis of TSC lesions.
SO - Am J Hum Genet 2001 Sep;69(3):493-503
AD - Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown, MA, USA.
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.
UI - 21412307
AU - Soucek T; Rosner M; Miloloza A; Kubista M; Cheadle JP; Sampson JR; Hengstschlager M
TI - Tuberous sclerosis causing mutants of the TSC2 gene product affect proliferation and p27 expression.
SO - Oncogene 2001 Aug 9;20(35):4904-9
AD - Obstetrics and Gynecology, University of Vienna, Prenatal Diagnosis and Therapy, Wahringer Gurtel 18-20, A-1090 Vienna, Austria.
The autosomal dominant disease tuberous sclerosis (TSC) is caused by mutations in either TSC1 on chromosome 9q34, encoding hamartin, or TSC2 on chromosome 16p13.3, encoding tuberin. TSC is characterized by hamartomas that occur in many organs of affected patients and these have been considered to likely result from defects in proliferation control. Although the true biochemical functions of the two TSC proteins have not been clarified, a series of independent investigations demonstrated that modulated hamartin or tuberin expression cause deregulation of proliferation/cell cycle in human, rodent and Drosophila cells. In support of tuberin acting as a tumor suppressor, ectopic overexpression of TSC2 has been shown to decrease proliferation rates of mammalian cells. Furthermore, overexpression of TSC2 has been demonstrated to trigger upregulation of the cyclin-dependent kinase inhibitor p27. We report that three different naturally occurring and TSC causing mutations within the TSC2 gene eliminate neither the anti-proliferative capacity of tuberin nor tuberin's effects on p27 expression. For the first time these data provide strong evidence that deregulation of proliferation and/or upregulation of p27 are not likely to be the primary/only mechanisms of hamartoma development in TSC. These results demand reassessment of previous hypotheses of the pathogenesis of TSC.
UI - 21393301
AU - Bane A; Tadesse Y
TI - Case of tuberous sclerosis.
SO - Ethiop Med J 2001 Apr;39(2):143-8
AD - Department of Internal Medicine, Faculty of Medicine, Addis Ababa University, P.O. Box 2380, Addis Ababa.
Tuberous Sclerosis (TSc) is a benign multi-system hamaertomatosis and is one of the neurocutaneous syndromes (2, 3, 7). The first case of tuberous sclerosis in a 27 years old female patient is reported from Ethiopia. The importance of meticulous evaluation of a patient as a whole to reach at the right diagnosis is stressed. The clinicopathological features of tuberous sclerosis are discussed with literature review.