Somatic chromosome abnormalities in the lungs of patients with pulmonary arterial hypertension

Micheala A. Aldred, Suzy A. Comhair, Marileila Varella-Garcia, Kewal Asosingh, Weiling Xu, George P. Noon, Patricia A. Thistlethwaite, Rubin M. Tuder, Serpil C. Erzurum, Mark W. Geraci, Christopher D. Coldren

Research output: Contribution to journalArticle

81 Citations (Scopus)

Abstract

Rationale: 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. Objectives: 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. Measurements and Main 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.

Original languageEnglish (US)
Pages (from-to)1153-1160
Number of pages8
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume182
Issue number9
DOIs
StatePublished - Nov 1 2010
Externally publishedYes

Fingerprint

Pulmonary Hypertension
Chromosome Aberrations
Lung
Endothelial Cells
Germ-Line Mutation
Pulmonary Artery
Smooth Muscle Myocytes
Chromosomes, Human, Pair 13
X Chromosome Inactivation
Genomic Instability
X Chromosome
Fluorescence In Situ Hybridization
Microsatellite Repeats
Methylation
Blood Vessels
Cell Proliferation
Genome
Growth
Population

Keywords

  • Chromosome deletion
  • Endothelium
  • Somatic genetics

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Aldred, M. A., Comhair, S. A., Varella-Garcia, M., Asosingh, K., Xu, W., Noon, G. P., ... Coldren, C. D. (2010). Somatic chromosome abnormalities in the lungs of patients with pulmonary arterial hypertension. American Journal of Respiratory and Critical Care Medicine, 182(9), 1153-1160. https://doi.org/10.1164/rccm.201003-0491OC

Somatic chromosome abnormalities in the lungs of patients with pulmonary arterial hypertension. / Aldred, Micheala A.; Comhair, Suzy A.; Varella-Garcia, Marileila; Asosingh, Kewal; Xu, Weiling; Noon, George P.; Thistlethwaite, Patricia A.; Tuder, Rubin M.; Erzurum, Serpil C.; Geraci, Mark W.; Coldren, Christopher D.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 182, No. 9, 01.11.2010, p. 1153-1160.

Research output: Contribution to journalArticle

Aldred, MA, Comhair, SA, Varella-Garcia, M, Asosingh, K, Xu, W, Noon, GP, Thistlethwaite, PA, Tuder, RM, Erzurum, SC, Geraci, MW & Coldren, CD 2010, 'Somatic chromosome abnormalities in the lungs of patients with pulmonary arterial hypertension', American Journal of Respiratory and Critical Care Medicine, vol. 182, no. 9, pp. 1153-1160. https://doi.org/10.1164/rccm.201003-0491OC
Aldred, Micheala A. ; Comhair, Suzy A. ; Varella-Garcia, Marileila ; Asosingh, Kewal ; Xu, Weiling ; Noon, George P. ; Thistlethwaite, Patricia A. ; Tuder, Rubin M. ; Erzurum, Serpil C. ; Geraci, Mark W. ; Coldren, Christopher D. / Somatic chromosome abnormalities in the lungs of patients with pulmonary arterial hypertension. In: American Journal of Respiratory and Critical Care Medicine. 2010 ; Vol. 182, No. 9. pp. 1153-1160.
@article{b4886dce693743db87213ef34051071a,
title = "Somatic chromosome abnormalities in the lungs of patients with pulmonary arterial hypertension",
abstract = "Rationale: 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. Objectives: 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. Measurements and Main 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.",
keywords = "Chromosome deletion, Endothelium, Somatic genetics",
author = "Aldred, {Micheala A.} and Comhair, {Suzy A.} and Marileila Varella-Garcia and Kewal Asosingh and Weiling Xu and Noon, {George P.} and Thistlethwaite, {Patricia A.} and Tuder, {Rubin M.} and Erzurum, {Serpil C.} and Geraci, {Mark W.} and Coldren, {Christopher D.}",
year = "2010",
month = "11",
day = "1",
doi = "10.1164/rccm.201003-0491OC",
language = "English (US)",
volume = "182",
pages = "1153--1160",
journal = "American Journal of Respiratory and Critical Care Medicine",
issn = "1073-449X",
publisher = "American Thoracic Society",
number = "9",

}

TY - JOUR

T1 - Somatic chromosome abnormalities in the lungs of patients with pulmonary arterial hypertension

AU - Aldred, Micheala A.

AU - Comhair, Suzy A.

AU - Varella-Garcia, Marileila

AU - Asosingh, Kewal

AU - Xu, Weiling

AU - Noon, George P.

AU - Thistlethwaite, Patricia A.

AU - Tuder, Rubin M.

AU - Erzurum, Serpil C.

AU - Geraci, Mark W.

AU - Coldren, Christopher D.

PY - 2010/11/1

Y1 - 2010/11/1

N2 - Rationale: 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. Objectives: 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. Measurements and Main 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.

AB - Rationale: 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. Objectives: 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. Measurements and Main 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.

KW - Chromosome deletion

KW - Endothelium

KW - Somatic genetics

UR - http://www.scopus.com/inward/record.url?scp=78349266115&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78349266115&partnerID=8YFLogxK

U2 - 10.1164/rccm.201003-0491OC

DO - 10.1164/rccm.201003-0491OC

M3 - Article

VL - 182

SP - 1153

EP - 1160

JO - American Journal of Respiratory and Critical Care Medicine

JF - American Journal of Respiratory and Critical Care Medicine

SN - 1073-449X

IS - 9

ER -