Constructing and validating a risk model based on neutrophil-related genes for evaluating prognosis and guiding immunotherapy in colon cancer

IF 3.2 4区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Journal of Gene Medicine Pub Date : 2024-04-15 DOI:10.1002/jgm.3684

Shasha Wang, Lili Wang, Mingxiu Qiu, Zhongkun Lin, Weiwei Qi, Jing Lv, Yan Wang, Yangyang Lu, Xiaoxuan Li, Wenzhi Chen, Wensheng Qiu

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引用次数: 0

Abstract

Background

Colon cancer is one of the most common digestive tract malignancies. Although immunotherapy has brought new hope to colon cancer patients, there is still a large proportion of patients who do not benefit from immunotherapy. Studies have shown that neutrophils can interact with immune cells and immune factors to affect the prognosis of patients.

Methods

We first determined the infiltration level of neutrophils in tumors using the CIBERSORT algorithm and identified key genes in the final risk model by Spearman correlation analysis and subsequent Cox analysis. The risk score of each patient was obtained by multiplying the Cox regression coefficient and the gene expression level, and patients were divided into two groups based on the median of risk score. Differences in overall survival (OS) and progression-free survival (PFS) were assessed by Kaplan–Meier survival analysis, and model accuracy was validated in independent dataset. Differences in immune infiltration and immunotherapy were evaluated by immunoassay. Finally, immunohistochemistry and western blotting were performed to verify the expression of the three genes in the colon normal and tumor tissues.

Results

We established and validated a risk scoring model based on neutrophil-related genes in two independent datasets, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database, with SLC11A1 and SLC2A3 as risk factors and MMP3 as a protective factor. A new nomogram was constructed and validated by combining clinical characteristics and the risk score model to better predict patients OS and PFS. Immune analysis showed that patients in the high-risk group had immune cell infiltration level, immune checkpoint level and tumor mutational burden, and were more likely to benefit from immunotherapy.

Conclusions

The low-risk group showed better OS and PFS than the high-risk group in the neutrophil-related gene-based risk model. Patients in the high-risk group presented higher immune infiltration levels and tumor mutational burden and thus may be more responsive to immunotherapy.

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构建并验证基于中性粒细胞相关基因的风险模型，以评估结肠癌预后并指导免疫疗法

背景结肠癌是最常见的消化道恶性肿瘤之一。尽管免疫疗法为结肠癌患者带来了新希望，但仍有很大一部分患者无法从免疫疗法中获益。研究表明，中性粒细胞可与免疫细胞和免疫因子相互作用，影响患者的预后。方法我们首先使用 CIBERSORT 算法确定肿瘤中性粒细胞的浸润水平，并通过 Spearman 相关性分析和随后的 Cox 分析确定最终风险模型中的关键基因。将Cox回归系数与基因表达水平相乘，得出每位患者的风险评分，并根据风险评分的中位数将患者分为两组。总生存期（OS）和无进展生存期（PFS）的差异通过 Kaplan-Meier 生存分析进行评估，并在独立数据集中验证了模型的准确性。免疫测定评估了免疫浸润和免疫治疗的差异。最后，通过免疫组化和免疫印迹技术验证了三个基因在结肠正常组织和肿瘤组织中的表达情况。结果我们在癌症基因组图谱（The Cancer Genome Atlas，TCGA）和基因表达总库（Gene Expression Omnibus，GEO）这两个独立的数据集中建立并验证了一个基于中性粒细胞相关基因的风险评分模型，其中SLC11A1和SLC2A3为风险因子，MMP3为保护因子。通过结合临床特征和风险评分模型，构建并验证了一个新的提名图，以更好地预测患者的OS和PFS。免疫分析表明，高风险组患者具有免疫细胞浸润水平、免疫检查点水平和肿瘤突变负荷，更有可能从免疫治疗中获益。结论在基于中性粒细胞相关基因的风险模型中，低风险组的OS和PFS均优于高风险组。高风险组患者的免疫浸润水平和肿瘤突变负荷较高，因此可能对免疫疗法更敏感。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Gene Medicine 医学-生物工程与应用微生物

CiteScore

6.40

自引率

0.00%

发文量

审稿时长

6-12 weeks

期刊介绍： The aims and scope of The Journal of Gene Medicine include cutting-edge science of gene transfer and its applications in gene and cell therapy, genome editing with precision nucleases, epigenetic modifications of host genome by small molecules, siRNA, microRNA and other noncoding RNAs as therapeutic gene-modulating agents or targets, biomarkers for precision medicine, and gene-based prognostic/diagnostic studies. Key areas of interest are the design of novel synthetic and viral vectors, novel therapeutic nucleic acids such as mRNA, modified microRNAs and siRNAs, antagomirs, aptamers, antisense and exon-skipping agents, refined genome editing tools using nucleic acid /protein combinations, physically or biologically targeted delivery and gene modulation, ex vivo or in vivo pharmacological studies including animal models, and human clinical trials. Papers presenting research into the mechanisms underlying transfer and action of gene medicines, the application of the new technologies for stem cell modification or nucleic acid based vaccines, the identification of new genetic or epigenetic variations as biomarkers to direct precision medicine, and the preclinical/clinical development of gene/expression signatures indicative of diagnosis or predictive of prognosis are also encouraged.