A DNA Damage Repair Gene Signature Associated With Immunotherapy Response and Clinical Prognosis in Clear Cell Renal Cell Carcinoma.
A DNA Damage Repair Gene Signature Associated With Immunotherapy Response and Clinical Prognosis in Clear Cell Renal Cell Carcinoma.
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与透明细胞肾细胞癌免疫治疗反应和临床预后相关的 DNA 损伤修复基因特征
DOI：
10.3389/fgene.2022.798846
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发表时间：
2022
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
背景：透明细胞肾细胞癌（ccRCC）是肾癌中最常见的亚型，临床预后相对较差。DNA损伤修复基因（DDRGs）作为潜在的生物标志物，在预测ccRCC的免疫治疗反应和临床预后方面很少有报道。方法：从TCGA数据库中收集ccRCC队列的RNA-seq和临床资料。采用单因素Cox回归和LASSO分析构建DDRG风险特征。功能富集分析用于探索与DDRG信号相关的潜在富集通路。采用基因集富集分析估计免疫细胞浸润水平，采用肿瘤免疫功能障碍和排斥（TIDE）算法预测ccRCC的免疫应答。为了预测1年、3年和5年的总生存期（OS），基于独立预后因素构建了nomogram，其表现将通过校准曲线进行评估。结果：在ccRCC队列中共鉴定出47个具有显著预后价值的DNA损伤修复相关基因（DDRGs） （n = 519）。通过LASSO分析，构建了由MSH3、RAD54L、RAD50、EME1、UNG和NEIL3 6个drg组成的DDRG风险特征。然后根据风险评分将ccRCC患者分为低危组和高危组。生存分析显示，正如测试数据集所证实的那样，高危组患者的OS和无进展生存期（PFS）明显较差。功能富集分析表明，高、低危组差异表达基因（DEGs）在ccRCC中主要与免疫相关的生物学过程相关，其中免疫缺陷途径在高危组显著富集。虽然风险信号与免疫细胞浸润显著相关，但DDRG信号中PD-1和PD-L1的表达较少，这可能表明高危组对免疫治疗的反应较差。此外，Cox回归分析表明，与临床特征相比，DDRG特征可以作为独立的预后预测因子。基于独立的预后预测因子，我们构建了一个对ccRCC患者OS预测具有良好预测能力的nomogram。结论：我们开发了一种可靠的DDRG风险标记，可以独立预测ccRCC的OS和PFS，也有望预测ccRCC患者的免疫治疗反应。
Background: Clear cell renal cell carcinoma (ccRCC) is the most common subtype in renal cell carcinoma with relatively poor clinical outcomes DNA damage repair genes (DDRGs) as potential biomarkers are rarely reported in predicting immunotherapy response and clinical prognosis for ccRCC. Methods: RNA-seq and clinical data of ccRCC cohort were collected form TCGA database. Univariate Cox regression and LASSO analysis were performed to construct a DDRG risk signature. Functional enrichment analysis was performed to explore latently enriched pathways associated with DDRG signature. Immune cell infiltration level was estimated using gene set enrichment analysis, and immune response of ccRCC was predicted by tumor immune dysfunction and exclusion (TIDE) algorithm. To predict 1-, 3-, and 5-years overall survival (OS), a nomogram was constructed based on independent prognostic factors, whose performance would be evaluated by calibration curve. Results: A total of 47 DNA damage repair related genes (DDRGs) with significant prognostic value were identified in the ccRCC cohort (n = 519). A DDRG risk signature comprising six DRRGs (MSH3, RAD54L, RAD50, EME1, UNG, and NEIL3) were constructed by the LASSO analysis. ccRCC patients were then divided into low- and high-risk groups based on the risk score. Survival analysis revealed that patients in high-risk groups exhibited significantly poorer OS and progression-free survival (PFS), as was confirmed by the testing dataset. Functional enrichment analysis indicated that differentially expressed genes (DEGs) between high- and low-risk groups were mainly associated with immune-related biological processes in ccRCC, among which the immunodeficiency pathway was significantly enriched in the high-risk group. Though the risk signature was significantly correlated with the immune cell infiltration, PD-1 and PD-L1 were less expressed in the DDRG signature, which might indicate the poor response to immunotherapy in the high-risk group. Furthermore, the Cox regression analysis indicated that the DDRG signature can be served as an independent prognostic predictor when compared to clinical characteristics. Based on the independent prognostic predictors, we constructed a nomogram with excellent predictive ability in OS prediction for ccRCC patients. Conclusion: We developed a reliable DDRG risk signature that can independently predict the OS and PFS of ccRCC, which is also promising for predicting immunotherapeutic responses in ccRCC patients.
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影响因子：
3.4
作者：
Warren AY;Harrison D
通讯作者：
Harrison D
影响因子：
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3.2
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影响因子：
5.7
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通讯作者：
Kolenko VM