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| Status |
Public on May 01, 2010 |
| Title |
Acquired chromosome abnormalities in the lungs of patients with Pulmonary Arterial Hypertension (Illumina) |
| Organism |
Homo sapiens |
| Experiment type |
Genome variation profiling by SNP array
SNP genotyping by SNP array
|
| Summary |
Vascular remodeling in pulmonary arterial hypertension (PAH) involves proliferation and migration of endothelial and smooth muscle cells, leading to obliterative vascular lesions. Previous studies have indicated that the endothelial cell proliferation is quasi-neoplastic, with evidence of monoclonality and instability of short DNA microsatellite sequences. To assess whether there is larger scale genomic instability, we performed genome-wide microarray copy number analysis on pulmonary artery endothelial (PAEC) and smooth muscle cells isolated from the lungs of PAH patients. Mosaic chromosomal abnormalities were detected in five of nine PAEC cultures from PAH lungs and zero of four controls. Fluorescent in situ hybridization analysis confirmed the presence of these abnormalities in vivo in two of three cases. One patient harbored a germline mutation of BMPR2, the primary genetic cause of PAH, and a somatic loss of chromosome-13, which constitutes a second hit in the same pathway by deleting Smad-8. In two female cases with mosaic loss of the X-chromosome, methylation analysis showed that the active X was deleted. Remarkably, one also showed completely skewed X-inactivation in the non-deleted cells, suggesting the PAEC population was clonal prior to the acquisition of the chromosome abnormality. Our data indicate a high frequency of genetically abnormal sub-clones within the lung vessels of patients with PAH and provide the first definitive evidence of a second genetic hit in a patient with a germline BMPR2 mutation. We propose that these chromosome abnormalities may confer a growth advantage and thus contribute to the progression of PAH.
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| Overall design |
Cross-sectional study of genomic copy number in cells cultured from the lungs of PAH patients.
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| Contributor(s) |
Aldred MA, Comhair SA, Varella-Garcia M, Asosingh K, Xu W, Noon GP, Thistlethwaite PA, Tuder RM, Erzurum SC, Geraci MW, Coldren CD |
| Citation(s) |
20581168 |
| |
| Submission date |
Mar 29, 2010 |
| Last update date |
Jan 30, 2015 |
| Contact name |
Christopher D Coldren |
| E-mail(s) |
Chris.Coldren@ucdenver.edu
|
| Phone |
303 724 6056
|
| Organization name |
University of Colorado School of Medicine
|
| Department |
Medicine
|
| Lab |
Pulmonary Sciences and Critical Care Medicine
|
| Street address |
12700 East 17th Place
|
| City |
Aurora |
| State/province |
CO |
| ZIP/Postal code |
80045 |
| Country |
USA |
| |
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| Platforms (3) |
| GPL5677 |
HumanHap300-2 v2.0 Genotyping BeadChip |
| GPL6985 |
Illumina HumanCNV370-QuadV3 DNA Analysis BeadChip (HumanCNV370-QuadV3_C) |
| GPL8887 |
Illumina Human610-Quad v1.0 BeadChip |
|
| Samples (24)
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| Relations |
| BioProject |
PRJNA126693 |
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