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Phenotypic characterization of disseminated cells with TSC2 loss of heterozygosity in patients with lymphangioleiomyomatosis.

Authors: Cai, X  Pacheco-Rodriguez, G  Fan, QY  Haughey, M  Samsel, L  El-Chemaly, S  Wu, HP  McCoy, JP  Steagall, WK  Lin, JP  Darling, TN  Moss, J 
Citation: Cai X, etal., Am J Respir Crit Care Med. 2010 Dec 1;182(11):1410-8. doi: 10.1164/rccm.201003-0489OC. Epub 2010 Jul 16.
Pubmed: (View Article at PubMed) PMID:20639436
DOI: Full-text: DOI:10.1164/rccm.201003-0489OC

RATIONALE: Lymphangioleiomyomatosis (LAM), occurring sporadically (S-LAM) or in patients with tuberous sclerosis complex (TSC), results from abnormal proliferation of LAM cells exhibiting mutations or loss of heterozygosity (LOH) of the TSC genes, TSC1 or TSC2. OBJECTIVES: To identify molecular markers useful for isolating LAM cells from body fluids and determine the frequency of TSC1 or TSC2 LOH. METHODS: Candidate cell surface markers were identified using gene microarray analysis of human TSC2(-)(/)(-) cells. Cells from bronchoalveolar lavage fluid (BALF), urine, chylous effusions, and blood were sorted based on reactivity with antibodies against these proteins (e.g., CD9, CD44v6) and analyzed for LOH using TSC1- and TSC2-related microsatellite markers and single nucleotide polymorphisms in the TSC2 gene. MEASUREMENTS AND MAIN RESULTS: CD44v6(+)CD9(+) cells from BALF, urine, and chyle showed TSC2 LOH in 80%, 69%, and 50% of patient samples, respectively. LAM cells with TSC2 LOH were detected in more than 90% of blood samples. LAM cells from different body fluids of the same patients showed, in most cases, identical LOH patterns, that is, loss of alleles at the same microsatellite loci. In a few patients with S-LAM, LAM cells from different body fluids differed in LOH patterns. No patients with S-LAM with TSC1 LOH were identified, suggesting that TSC2 abnormalities are responsible for the vast majority of S-LAM cases and that TSC1-disease may be subclinical. CONCLUSIONS: Our data support a common genetic origin of LAM cells in most patients with S-LAM, consistent with a metastatic model. In some cases, however, there was evidence for genetic heterogeneity between LAM cells in different sites or within a site.


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CRRD Object Information
CRRD ID: 11568662
Created: 2016-12-09
Species: All species
Last Modified: 2016-12-09
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.