Somatic Mutations: The Next Frontier in Demystifying Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis?
Somatic Mutations: The Next Frontier in Demystifying Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis?
复制标题
体细胞突变：揭开慢性阻塞性肺疾病和特发性肺纤维化神秘面纱的下一个前沿？
DOI：
10.1164/rccm.202310-1774ed
复制
发表时间：
2023
影响因子：
24.7
通讯作者：
Kaminski,Naftali
中科院分区：
文献类型：
--
作者：
Yan,Xiting;Kaminski,Naftali
许多慢性肺部疾病（如慢性阻塞性肺疾病（COPD）和特发性肺纤维化（IPF））的发病机制是由遗传易感性、环境暴露和衰老的复杂相互作用驱动的。虽然我们对遗传基因突变与COPD（1）和IPF（2）的关联的理解取得了惊人的进展，但实际上对体细胞突变没有兴趣，体细胞突变是在生物体的一生中积累的细胞DNA的变化，这通常反映了环境暴露的影响，现在越来越多地在非恶性复杂疾病中进行研究（3）。在本期杂志中，Yun和他的同事（pp. 1196-1205）应用相对新颖的方法来解决这种未满足的需求（4）。他们没有进行全基因组DNA测序，而是从肺组织研究联盟收集的1，251名受试者的肺样本的批量RNA测序数据中进行SNP调用分析，包括无疾病对照受试者和慢性肺部疾病（主要是COPD和IPF）患者。虽然DNA测序是执行此任务的最终方法，但RNA测序数据提供了表达基因组的序列内容信息，并已成功用于检测癌症和非癌症条件中的体细胞突变（5）。配对的全基因组测序数据也可用于分析样本，使作者能够将体细胞突变与种系突变分开。体细胞突变负荷定义为体细胞突变总数，与疾病组、肺功能、细胞组成、吸烟和实际年龄相关。发现IPF患者的体细胞突变负荷显著高于COPD患者和正常对照受试者。在所有受试者以及疾病亚组中，肺功能（通过FEV 1和FVC评估）与突变负荷呈负相关。使用最先进的方法对批量RNA测序数据进行去卷积，以推断每个样品中的细胞类型组成。基于去卷积，对气道上皮细胞、肺泡上皮细胞、异常基底细胞以及基质细胞、免疫细胞和内皮细胞的相对丰度进行定量。突变负荷与气道上皮细胞、内皮细胞和免疫细胞的比例呈正相关，与肺泡上皮细胞的比例呈负相关，但与基质细胞无关。异常基底细胞样细胞的相对丰度也与疾病中的突变负荷相关。在校正了年龄、性别、种族、吸烟史和总映射读数的多变量回归分析中，气道/肺泡上皮比和肺功能（FEV 1，FVC）与突变负荷具有统计学显著性和独立相关性。这些细胞组成的相关性可能表明气道上皮细胞的潜在体细胞克隆扩增，气道上皮细胞是具有较高细胞增殖速率的高转换细胞，导致更多的体细胞突变积累，但也可能反映基因表达或细胞丰度的变化。先前在IPF和COPD中均报告了肺泡上皮细胞损失（6，7）。除了突变负担之外，作者还将所鉴定的体细胞突变与疾病组、种系突变和癌症驱动基因相关联。当将鉴定的体细胞突变与癌症驱动基因进行比较时，COPD患者显示出比正常对照受试者显著更高的癌症驱动基因突变比例。IPF患者有类似的趋势，但没有...
The pathogenesis of many chronic lung diseases, such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), is driven by the complex interplay of genetic susceptibility, environmental exposures, and aging. Although there has been amazing progress in our understanding of the association of inherited gene mutations with COPD (1) and IPF (2), there has literally been no interest in somatic mutations, changes in cellular DNA that accumulate through the lifetime of the organism, which quite often reflect the impact of environmental exposures and are now increasingly studied in nonmalignant complex diseases (3). In this issue of the Journal, Yun and colleagues (pp. 1196–1205) apply a relatively novel approach to address this unmet need (4). Instead of performing whole-genome DNA sequencing, they conducted SNP calling analysis from bulk RNA sequencing data of lung samples from 1,251 subjects, including disease-free control subjects and patients with chronic lung diseases (mainly COPD and IPF), collected by the Lung Tissue Research Consortium. Although DNA sequencing is the ultimate way to perform this task, RNA sequencing data provide sequence content information of the expressed genome and have been used successfully to detect somatic mutations in cancer and noncancer conditions (5). Paired wholegenome sequencing data were also available for the analyzed samples, enabling the authors to separate somatic mutations from germline mutations. The somatic mutational burden, defined as the total number of somatic mutations, was associated with disease group, lung function, cellular composition, smoking, and chronological age. Patients with IPF were found to have a significantly higher somatic mutational burden than both patients with COPD and normal control subjects. Lung functions, assessed by both FEV1 and FVC, were inversely associated with the mutational burden in all subjects as well as in disease subgroups. The bulk RNA sequencing data were deconvolved using state-of-the-art methods to infer cell-type composition in each sample. The relative abundance of airway epithelial cells, alveolar epithelial cells, aberrant basaloid cells, and stromal, immune, and endothelial cells was quantified based on the deconvolution. Mutational burden was positively correlated with the proportion of airway epithelial, endothelial, and immune cells and inversely correlated with the proportion of alveolar epithelial cells but not stromal cells. The relative abundance of aberrant basaloid cells also correlated with mutational burden in disease. In multivariable regression analysis adjusted for age, sex, race, smoking history, and total mapped reads, both airway/alveolar epithelial ratio and lung function (FEV1, FVC) were statistically significantly and independently associated with mutational burden. These associations of cellular compositions may indicate potential somatic clonal expansions of airway epithelial cells, which are the high-turnover cells with a higher cellular proliferation rate leading to more accumulation of somatic mutations, but could also reflect changes in gene expression or cellular abundance. Loss of alveolar epithelial cells has been previously reported in both IPF and COPD (6, 7). In addition to the mutational burden, the authors also associated the identified somatic mutations with disease group, germline mutations, and cancer driver genes. When comparing the identified somatic mutations to cancer driver genes, patients with COPD showed a significantly higher proportion of cancer driver gene mutations than normal control subjects. Patients with IPF had a similar trend but did not …