title: Somatic chromosome abnormalities in the lungs of patients with pulmonary arterial hypertension.
abstract: BACKGROUND
  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 quasineoplastic, with evidence of monoclonality and instability of short DNA microsatellite sequences.
  
  
  OBJECTIVE
  To assess whether there is larger-scale genomic instability.
  
  
  METHODS
  We performed genome-wide microarray copy number analysis on pulmonary artery endothelial cells and smooth muscle cells isolated from the lungs of patients with PAH.
  
  
  RESULTS
  Mosaic chromosomal abnormalities were detected in PAEC cultures from five of nine PAH lungs but not in normal (n = 8) or disease control subjects (n = 5). 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 somatic loss of chromosome-13, which constitutes a second hit in the same pathway by deleting Smad-8. In two female subjects with mosaic loss of the X chromosome, methylation analysis showed that the active X was deleted. One subject also showed completely skewed X-inactivation in the nondeleted cells, suggesting the pulmonary artery endothelial cell population was clonal before the acquisition of the chromosome abnormality.
  
  
  CONCLUSIONS
  Our data indicate a high frequency of genetically abnormal subclones within PAH lung vessels 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.
authors.affiliation: Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA. aldredm@ccf.org
authors.forename: Micheala A
authors.initials: MA
authors.lastname: Aldred
authors.forename: Suzy A
authors.initials: SA
authors.lastname: Comhair
authors.forename: Marileila
authors.initials: M
authors.lastname: Varella-Garcia
authors.forename: Kewal
authors.initials: K
authors.lastname: Asosingh
authors.forename: Weiling
authors.initials: W
authors.lastname: Xu
authors.forename: George P
authors.initials: GP
authors.lastname: Noon
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Thistlethwaite
authors.forename: Rubin M
authors.initials: RM
authors.lastname: Tuder
authors.forename: Serpil C
authors.initials: SC
authors.lastname: Erzurum
authors.forename: Mark W
authors.initials: MW
authors.lastname: Geraci
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Coldren
mesh_terms: D000328:Adult; D056151:Airway Remodeling / Q000502:physiology*; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics*; D049109:Cell Proliferation; D002648:Child; D002869:Chromosome Aberrations; D002872:Chromosome Deletion; D056915:DNA Copy Number Variations; D042783:Endothelial Cells / Q000473:pathology / Q000502:physiology; D005260:Female; D015321:Gene Rearrangement; D055106:Genome-Wide Association Study; D042822:Genomic Instability; D018095:Germ-Line Mutation; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000473:pathology*; D017404:In Situ Hybridization, Fluorescence; D008168:Lung / Q000166:cytology; D046228:Microarray Analysis; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D011651:Pulmonary Artery / Q000166:cytology / Q000502:physiology; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics / Q000473:pathology; D049951:X Chromosome Inactivation
chemical_list: C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II