title: Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis.
abstract: Lymphangioleiomyomatosis (LAM) is a progressive and often fatal interstitial lung disease characterized by a diffuse proliferation of abnormal smooth muscle cells in the lungs. LAM is of unusual interest biologically because it affects almost exclusively young women. LAM can occur as an isolated disorder (sporadic LAM) or in association with tuberous sclerosis complex. Renal angiomyolipomas, which are found in most tuberous sclerosis patients, also occur in 60% of sporadic LAM patients. We previously found TSC2 loss of heterozygosity in 7 of 13 (54%) of angiomyolipomas from sporadic LAM patients, suggesting that LAM and TSC could have a common genetic basis. In this study, we report the identification of somatic TSC2 mutations in five of seven angiomyolipomas from sporadic LAM patients. In all four patients from whom lung tissue was available, the same mutation found in the angiomyolipoma was present in the abnormal pulmonary smooth muscle cells. In no case was the mutation present in normal kidney, morphologically normal lung, or lymphoblastoid cells. Our data demonstrate that somatic mutations in the TSC2 gene occur in the angiomyolipomas and pulmonary LAM cells of women with sporadic LAM, strongly supporting a direct role of TSC2 in the pathogenesis of this disease.
authors.affiliation: Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia PA 19111, USA.
authors.forename: T
authors.initials: T
authors.lastname: Carsillo
authors.forename: A
authors.initials: A
authors.lastname: Astrinidis
authors.forename: E P
authors.initials: EP
authors.lastname: Henske
mesh_terms: D000328:Adult; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007668:Kidney / Q000737:chemistry; D008175:Lung Neoplasms / Q000235:genetics*; D018192:Lymphangioleiomyomatosis / Q000235:genetics*; D009130:Muscle, Smooth / Q000737:chemistry; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics*; D017354:Point Mutation; D012097:Repressor Proteins / Q000235:genetics*; D017384:Sequence Deletion; D014402:Tuberous Sclerosis / Q000235:genetics*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins
chemical_list: D004273:DNA, Neoplasm; D012097:Repressor Proteins; C000624653:TSC2 protein, human; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins