Identification of prognostic immune-related gene signature associated with tumor microenvironment of colorectal cancer

Wang, Yuanyuan; Li, Wei; Jin, Xiaojing; Jiang, Xia; Guo, Shang; Xu, Fei; Su, Xingkai; Wang, Guiqi; Zhao, Zhenze; Gu, Xiaosong

doi:10.1186/s12885-021-08629-3

Cited by 16 publications

(10 citation statements)

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“…In recent years, multiple gene signature-based risk assessment models have been increasingly used for predicting the prognosis of CRC patients ( Yang et al, 2020 ; Yuan et al, 2021 ; Yue et al, 2021 ), which can provide more accurate prediction of prognosis and survival than single gene biomarker. Furthermore, the utilization of mRNA signatures based on tumor and microenvironment features has a better predictive effect on CRC ( Zhu et al, 2020 ; Wang et al, 2021 ). However, few study has been concerned on the prognosis potential of ferroptosis-associated gene signatures in CRC.…”

Section: Discussionmentioning

confidence: 99%

A ferroptosis associated gene signature for predicting prognosis and immune responses in patients with colorectal carcinoma

et al. 2022

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Background: Colorectal carcinoma (CRC) is one of the most prevalent malignancies globally. Ferroptosis, a novel type of cell death, is critical in the development and treatment of tumors.Objective: This study was designed to establish a genetic signature for ferroptosis which has a predictive effect on the outcomes and immunotherapeutic response of CRC.Methods: Data of CRC patients were retrieved from TCGA and GEO databases. The genes associated with ferroptosis were obtained from GeneCards. The genetic signature for ferroptosis was identified by performing Cox regression analysis. Kaplan–Meier and ROC analysis were performed to assess the prognosis role of the genetic signature. CIBERSORT tool was used to identify a potential association of the genetic signature with the immune cells. The potential immunotherapeutic signatures and drug sensitivity prediction targeting this signature were also discussed. Immunohistochemistry was used to detect expression of ferroptosis-associated genes in CRC tissues and adjacent tissues.Results: A ferroptosis-associated gene signature comprised of three genes (CDKN2A, FDFT1, and ACSL6) was developed for prediction of prognosis and evaluation of immune responses in CRC. Patients in the high-risk group tended to have a poor prognosis. In CRC, the ferroptosis-associated gene signature may function as independent predictors. Additionally, the expressional levels of the immune checkpoint proteins PD-L1 and CTLA-4 were substantially increased in the high-risk group. Moreover, we can distinguish between patients based on their immunotherapeutic responses more effectively if we categorize them by this signature. Additionally, candidate compounds were identified for the differentiation of CRC subtypes.Conclusion: The ferroptosis-associated gene signature identified in this study is effective in predicting the prognosis and evaluating immunotherapeutic response in CRC patients, and provides us with novel insights into the potential effect of ferroptosis targeted treatment on CRC.

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Section: Discussionmentioning

confidence: 99%

A ferroptosis associated gene signature for predicting prognosis and immune responses in patients with colorectal carcinoma

et al. 2022

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“…The scores of stromal cell and immune cell between stage I and stage III, stage IV were remarkably different, suggesting that the change of tumor microenvironment promoted the progression of tumor from early onset to middle and late stage. Immune infiltration and stromal cell analyses showed that the prognostic value of the risk model was related to the CRC immune system ( Liu et al, 2021 ; Wang et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

A Prognostic Model Using Immune-Related Genes for Colorectal Cancer

Wei

Zhang

Liu

et al. 2022

Front. Cell Dev. Biol.

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There is evidence suggesting that immune genes play pivotal roles in the development and progression of colorectal cancer (CRC). Colorectal carcinoma patient data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) were randomly classified into a training set, a test set, and an external validation set. Differentially expressed gene (DEG) analyses, univariate Cox regression, and the least absolute shrinkage and selection operator (LASSO) were used to identify survival-associated immune genes and develop a prognosis model. Receiver operating characteristic (ROC) analysis and principal component analysis (PCA) were used to evaluate the discrimination of the risk models. The model genes predicted were verified using the Human Protein Atlas (HPA) databases, colorectal cell lines, and fresh CRC and adjacent tissues. To understand the relationship between IRGs and immune invasion and the TME, we analyzed the content of immune cells and scored the TME using CIBERSORT and ESTIMATE algorithms. Finally, we predicted the potential sensitive chemotherapeutic drugs in different risk score groups by the Genomics of Drug Sensitivity in Cancer (GDSC). A total of 491 IRGs were screened, and 14 IRGs were identified to be significantly related to overall survival (OS) and applied to construct an immune-related gene (IRG) prognostic signature (IRGSig) for CRC patients. Calibration plots showed that nomograms have powerful predictive ability. PCA and ROC analysis further verified the predictive value of this fourteen-gene prognostic model in three independent databases. Furthermore, we discovered that the tumor microenvironment changed significantly during the tumor development process, from early to middle to late stage, which may be an essential factor for tumor deterioration. Finally, we selected six commonly used chemotherapeutic drugs that have the potential to be useful in the treatment of CRC. Altogether, immune genes were used to construct a prognosis model for CRC patients, and a variety of methods were used to test the accuracy of this model. In addition, we explored the immune mechanisms of CRC through immune cell infiltration and TME in CRC. Furthermore, we assessed the therapeutic sensitivity of many commonly used chemotherapeutic medicines in individuals with varying risk factors. Finally, the immune risk model and immune mechanism of CRC were thoroughly investigated in this paper.

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“…We used the R package ConsensusClusterPlus (ConsensusClusterPlus, RRID : SCR_016954) for consistent clustering analysis and DESeq2 (DESeq, RRID : SCR_000154)for identification of differentially expressed genes (DEGs). To determine the optimal number of clusters, we evaluated the results using cumulative distribution function and incremental area analysis with different clusters (2)(3)(4)(5)(6)(7)(8)(9)(10). The DEGs with fold change > 1.5 and FDR < 0.05 were defined as subtype-specific.…”

Section: Consistent Clustering Analysis and Identification Of Differe...mentioning

confidence: 99%

“…Utilize glycolysis as the main source of energy metabolism to obtain a higher sugar-breaking capacity, allowing the conversion of glucose to lactate to generate adenosine triphosphate (ATP) (8). Recently, an increasing number of studies have indicated that the TME, including lactate as well as immune microenvironments, affects the progression of CRC as well as its clinical outcomes (9,10). Incidentally, tumor cells exhibit an aberrant increase in glycolysis, which generates a high concentration of lactic acid that is necessary for malignant proliferation.…”

Section: Introductionmentioning

confidence: 99%

Lactate: A regulator of immune microenvironment and a clinical prognosis indicator in colorectal cancer

et al. 2022

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Lactate can play an immunosuppressive role in the tumor microenvironment and promote tumor development by recruiting and inducing the activity of immunosuppressive cells and molecules. High lactate concentrations are important for tumor cell metastasis, angiogenesis, and treatment resistance. With the in-depth studies on tumor metabolism, lactate, one of the key factors involved in glycolysis, has been increasing emerged its characteristic clinical value in colorectal cancer (CRC). In this study, lactate genes were screened based on lactate metabolism pathways. Subsequently, the lactate subtypes were determined by clustering and analysis of the subtypes at all levels, including immune checkpoints, immune infiltration, and clinical characteristics, which revealed the biological significance of lactate metabolism in CRC. Subtype-based differential gene analysis resulted in a lactate score, which stratifies the prognosis of CRC. We discovered that 27 lactate genes and 61 lactate-phenotype genes are associated with immune cell infiltration and have a significant prognostic efficacy. The CRC patients were clustered into four subtypes and five clusters, based on lactate genes and lactate-phenotype genes, respectively. There are significant differences in survival time and activities of hallmark pathways, namely immune-related signatures and chemokines, among these subtypes and clusters. Particularly, cluster 2 and subtype 1 have significantly higher lactate scores than that of the others. In conclusion, lactate score is an independent prognostic factor for cancer that can be used as a clinical guide for predicting CRC progression and as an evaluation factor for the effect of immunotherapy in CRC.

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Identification of prognostic immune-related gene signature associated with tumor microenvironment of colorectal cancer

Cited by 16 publications

References 50 publications

A ferroptosis associated gene signature for predicting prognosis and immune responses in patients with colorectal carcinoma

A ferroptosis associated gene signature for predicting prognosis and immune responses in patients with colorectal carcinoma

A Prognostic Model Using Immune-Related Genes for Colorectal Cancer

Lactate: A regulator of immune microenvironment and a clinical prognosis indicator in colorectal cancer

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