Lin Gaoteng, Feng Qingfu, Zhan Fangfang, Yang Fan, Niu Yuanjie, Li Gang
Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China.
Department of Neurology, The Affiliated Hospital of Putian University, Putian, China.
Front Genet. 2022 Feb 24;13:809794. doi: 10.3389/fgene.2022.809794. eCollection 2022.
Pyroptosis is a programmed cell death caused by inflammasomes, which is closely related to immune responses and tumor progression. The present study aimed to construct dual prognostic indices based on pyroptosis-associated and immune-associated genes and to investigate the impact of the biological signatures of these genes on Kidney Renal Clear Cell Carcinoma (KIRC). All the KIRC samples from the Cancer Genome Atlas (TCGA) were randomly and equally divided into the training and testing datasets. Cox and Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis were used to screen crucial pyroptosis-associated genes (PAGs), and a pyroptosis-associated genes prognostic index (PAGsPI) was constructed. Immune-associated genes (IAGs) related to PAGs were identified, and then screened through Cox and LASSO regression analyses, and an immune-associated genes prognostic index (IAGsPI) was developed. These two prognostic indices were verified by using the testing and the Gene Expression Omnibus (GEO) datasets and an independent cohort. The patients' response to immunotherapy was analyzed. A nomogram was constructed and calibrated. qRT-PCR was used to detect the expression of PAGs and IAGs in the tumor tissues and normal tissues. Functional experiment was carried out. 86 PAGs and 1,774 differentially expressed genes (DEGs) were obtained. After intersecting PAGs with DEGs, 22 differentially expressed PAGs (DEPAGs) were included in Cox and LASSO regression analyses, identifying 5 crucial PAGs. The PAGsPI was generated. Patients in the high-PAGsPI group had a poor prognosis. 82 differentially expressed IAGs (DEIAGs) were highly correlated with DEPAGs. 7 key IAGs were screened out, and an IAGsPI was generated. Patients in the high-IAGsPI group had a poor prognosis. PAGsPI and IAGsPI were verified to be robust and reliable. The results revealed patients in low-PAGsPI group and high-IAGsPI group may be more sensitive to immunotherapy. The calibrated nomogram was proved to be reliable. An independent cohort study also proved that PAGsPI and IAGsPI performed well in prognosis prediction. We found that the expression of AIM2 may affect proliferation of KIRC cells. PAGsPI and IAGsPI could be regarded as potential biomarkers for predicting the prognosis of patients with KIRC.
细胞焦亡是一种由炎性小体引起的程序性细胞死亡，与免疫反应和肿瘤进展密切相关。本研究旨在构建基于细胞焦亡相关基因和免疫相关基因的双重预后指标，并研究这些基因的生物学特征对肾透明细胞癌（KIRC）的影响。来自癌症基因组图谱（TCGA）的所有KIRC样本被随机且等分为训练数据集和测试数据集。使用Cox回归分析和最小绝对收缩与选择算子（LASSO）回归分析筛选关键的细胞焦亡相关基因（PAG），并构建细胞焦亡相关基因预后指数（PAGsPI）。鉴定与PAG相关的免疫相关基因（IAG），然后通过Cox回归分析和LASSO回归分析进行筛选，并开发免疫相关基因预后指数（IAGsPI）。使用测试数据集和基因表达综合数据库（GEO）数据集以及一个独立队列对这两个预后指标进行验证。分析患者对免疫疗法的反应。构建并校准列线图。使用qRT-PCR检测肿瘤组织和正常组织中PAG和IAG的表达。进行功能实验。获得了86个PAG和1774个差异表达基因（DEG）。将PAG与DEG进行交叉分析后，22个差异表达的PAG（DEPAG）纳入Cox回归分析和LASSO回归分析，确定了5个关键的PAG。生成了PAGsPI。高PAGsPI组的患者预后较差。82个差异表达的IAG（DEIAG）与DEPAG高度相关。筛选出7个关键IAG，并生成IAGsPI。高IAGsPI组的患者预后较差。PAGsPI和IAGsPI被验证具有稳健性和可靠性。结果显示，低PAGsPI组和高IAGsPI组的患者可能对免疫疗法更敏感。校准后的列线图被证明是可靠的。一项独立队列研究也证明，PAGsPI和IAGsPI在预后预测方面表现良好。我们发现AIM2的表达可能影响KIRC细胞的增殖。PAGsPI和IAGsPI可被视为预测KIRC患者预后的潜在生物标志物。
