Somatic Chromosome Abnormalities in the Lungs of Patients with Pulmonary Arterial Hypertension
Somatic Chromosome Abnormalities in the Lungs of Patients with Pulmonary Arterial Hypertension
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DOI：
10.1164/rccm.201003-0491oc
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发表时间：
2010-11-01
影响因子：
24.7
通讯作者：
Coldren, Christopher D.
中科院分区：
文献类型：
--
作者：
Aldred, Micheala A.;Comhair, Suzy A.;Coldren, Christopher D.
基本原理：肺动脉高压（PAH）的血管重塑涉及内皮细胞和平滑肌细胞的增殖和迁移，导致闭塞性血管病变。以往的研究表明，内皮细胞的增殖是准周期性的，有证据表明，单克隆性和不稳定性的短DNA微卫星序列。目的：评估是否有较大规模的基因组不稳定性。方法：我们进行了全基因组微阵列拷贝数分析肺动脉内皮细胞和平滑肌细胞分离自肺动脉高压患者的肺。测量和主要结果：在9个PAH肺中的5个肺的PAEC培养物中检测到镶嵌染色体异常，但在正常（n = 8）或疾病对照受试者（n = 5）中未检测到。荧光原位杂交分析证实了这些异常的存在下，在体内的三个案件。1例患者携带BMPR 2的生殖系突变（PAH的主要遗传原因）和13号染色体的体细胞丢失，这构成了通过删除Smad-8在同一途径中的第二次打击。在两名X染色体嵌合缺失的女性受试者中，甲基化分析显示活性X被删除。一个主题也表现出完全歪斜的X-失活的nondeleted细胞，这表明肺动脉内皮细胞群体是克隆前收购的染色体abnormality.Conclusions：我们的数据表明高频率的遗传异常的亚克隆肺动脉高压肺血管内，并提供第一个明确的证据，第二个基因击中患者的生殖系BMPR 2突变。我们认为，这些染色体异常可能赋予生长优势，从而有助于PAH的进展。
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.