Wu Nan, Liu Sixue, Li Jingjing, Hu Zhenyu, Yan Shi, Duan Hongwei, Wu Dafei, Ma Yuanyuan, Li Shaolei, Wang Xing, Wang Yaqi, Li Xiang, Lu Xuemei
Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Surgery II, Peking University Cancer Hospital & Institute, Beijing, China.
Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
Transl Lung Cancer Res. 2021 Mar;10(3):1239-1255. doi: 10.21037/tlcr-20-1086.
The concept of multi-step progression from atypical adenomatous hyperplasia (AAH) to invasive adenocarcinoma (ADC) has been proposed, and ground-glass nodules (GGNs) may play a critical role during the early lung tumorigenesis. We present the first comprehensive description of the genomic architecture of GGNs to unravel the genetic basis of GGN.
We investigated 30 GGN-like lungs ADC by performing >1,000× whole-exome sequencing (WES) and characterized the genomic variations and evaluate the relationship between the clinicopathologic and molecular characteristics in this disease.
Despite the low somatic mutation burden, GGNs exhibited high intratumor heterogeneity (ITH) characterized by the proportion of subclonal mutations. Different mutagenesis shaped the genomes of GGN during cancer evolution and were mostly featured by molecular clock-like signatures that occur in clonal mutations and defective DNA mismatch signatures that occur in subclonal mutations. Moreover, 10.7-67.1% clonal mutations occurred after whole-genome doubling (WGD), indicating that WGD could be a frequent truncal event in GGNs. Samples with WGD showed higher genomic instability but lower ITH. These GGNs were characterized by recurrent focal copy-number changes that are highly associated with tumorigenesis, with only two genes ( and ) that were recurrently mutated. Additionally, GGNs with different pathological subtypes or computed tomography (CT) features exhibited distinct genetic characteristics. Lepidic predominant or pure GGNs in CT images carried a lower mutation burden and had a relatively stable genome than nonlepidic or mixed GGNs. GGNs with mutations tended to accompany a pathologically lepidic pattern, indicating may drive the distinct subtype of lung cancer with better prognosis.
These findings facilitated interpreting the genomic characteristics of GGNs, provided insight into the early stages of lung cancer evolution, and possessed potential clinical significance.
已提出从非典型腺瘤样增生（AAH）到浸润性腺癌（ADC）的多步骤进展概念，磨玻璃结节（GGN）可能在早期肺癌发生过程中起关键作用。我们首次全面描述了GGN的基因组结构，以阐明GGN的遗传基础。
我们通过进行>1000×全外显子测序（WES）研究了30例GGN样肺ADC，并对基因组变异进行了表征，评估了该疾病临床病理特征与分子特征之间的关系。
尽管体细胞突变负担较低，但GGN表现出以亚克隆突变比例为特征的高肿瘤内异质性（ITH）。不同的诱变作用在癌症进化过程中塑造了GGN的基因组，其主要特征是克隆突变中出现的分子钟样特征和亚克隆突变中出现的缺陷DNA错配特征。此外，10.7%-67.1%的克隆突变发生在全基因组加倍（WGD）之后，这表明WGD可能是GGN中常见的主干事件。发生WGD的样本显示出更高的基因组不稳定性，但ITH较低。这些GGN的特征是反复出现的局灶性拷贝数变化，这与肿瘤发生高度相关，只有两个基因（和）反复发生突变。此外，具有不同病理亚型或计算机断层扫描（CT）特征的GGN表现出不同的遗传特征。CT图像中以鳞屑为主或纯GGN的突变负担较低，基因组比非鳞屑或混合GGN相对稳定。携带突变的GGN往往伴有病理鳞屑样模式，表明可能驱动预后较好的肺癌不同亚型。
这些发现有助于解释GGN的基因组特征，深入了解肺癌进化的早期阶段，并具有潜在的临床意义。
