Shan Guangyao, Bi Guoshu, Bian Yunyi, Valeria Besskaya, Zeng Dejun, Zhang Huan, Yao Guangyu, Zhang Yi, Fan Hong, Zhan Cheng
Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
Department of Thoracic Surgery, Zhongshan Hospital, Fudan University (Xiamen Branch), Xiamen, China.
Front Oncol. 2022 Feb 28;12:843528. doi: 10.3389/fonc.2022.843528. eCollection 2022.
Identified as a hallmark of cancer, the dysregulated cell cycle progression plays an important role in the promotion and progression of lung adenocarcinoma (LUAD). However, the genomic and microenvironment differences between cell cycle progression pathway altered/non-altered LUAD patients remain to be elucidated.
Data of this study were obtained from The Cancer Genome Atlas (TCGA), including simple nucleotide variation, copy number variation (CNV), RNA-seq gene expression, miRNA expression, survival, and clinical information. Besides, 34 LUAD samples from our institution were used as a validation cohort. Differentially expressed genes (DEGs), enrichment analysis, and immune cell infiltration were detected. At last, we built a LASSO-binary Logistic regression model to predict the cell-cycle-related gene mutation (CDKN2A, CCND1, CDK4, CCNE1, and RB1) in LUAD patients and further verified it in the samples from our institution.
Based on the cell cycle progression pathway status, the LUAD patients were divided into the mutation (n=322) and wild (n=46) groups. Compared to the wild group, the mutation group had a higher mutational load and CNV. Among the 16684 protein-coding genes analyzed, 302 were upregulated, and 354 were downregulated in the mutation group. Enrichment analysis indicated that these DEGs were closely related to metabolism items. After performing immune cell infiltration analysis of 22 immune cells, we found the proportion of 5 immune cells such as monocytes (P<0.01) and dendritic cells (P<0.01) were higher in the wild group. Finally, a cell-cycle-related 15-signature model was built by LASSO-Logistic regression analysis, which could predict the cell cycle progression pathway-related gene mutation (CDKN2A, CCND1, CDK4, CCNE1, and RB1) in LUAD patients. The validation cohorts showed the sensitivity and specificity of this model were 0.667 and 0.929, respectively.
The genomic and microenvironment characteristics differed between the cell cycle progression pathway altered/non-altered patients with LUAD. Our findings may provide new insight into personalized treatment for LUAD patients.
细胞周期进程失调被认为是癌症的一个标志，在肺腺癌（LUAD）的发生和发展中起重要作用。然而，细胞周期进程途径改变/未改变的LUAD患者之间的基因组和微环境差异仍有待阐明。
本研究的数据来自癌症基因组图谱（TCGA），包括单核苷酸变异、拷贝数变异（CNV）、RNA测序基因表达、miRNA表达、生存和临床信息。此外，来自我们机构的34例LUAD样本用作验证队列。检测差异表达基因（DEG）、富集分析和免疫细胞浸润。最后，我们构建了一个LASSO二元逻辑回归模型来预测LUAD患者的细胞周期相关基因突变（CDKN2A、CCND1、CDK4、CCNE1和RB1），并在我们机构的样本中进一步验证。
根据细胞周期进程途径状态，将LUAD患者分为突变组（n = 322）和野生组（n = 46）。与野生组相比，突变组具有更高的突变负荷和CNV。在分析的16684个蛋白质编码基因中，突变组中有302个上调，354个下调。富集分析表明这些DEG与代谢项目密切相关。在对22种免疫细胞进行免疫细胞浸润分析后，我们发现野生组中单核细胞（P < 0.01）和树突状细胞（P < 0.01）等5种免疫细胞的比例更高。最后，通过LASSO逻辑回归分析建立了一个与细胞周期相关的15个特征的模型，该模型可以预测LUAD患者中细胞周期进程途径相关基因突变（CDKN2A、CCND1、CDK4、CCNE1和RB1）。验证队列显示该模型的敏感性和特异性分别为0.667和0.929。
细胞周期进程途径改变/未改变的LUAD患者之间的基因组和微环境特征存在差异。我们的研究结果可能为LUAD患者的个性化治疗提供新的见解。
