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Immune-related gene expression signatures in colorectal cancer.

ABSTRACT: The immune system is crucial in regulating colorectal cancer (CRC) tumorigenesis. Identification of immune-related transcriptomic signatures derived from the peripheral blood of patients with CRC would provide insights into CRC pathogenesis, and suggest novel clues to potential immunotherapy strategies for the disease. The present study collected blood samples from 59 patients with CRC and 62 healthy control patients and performed whole blood gene expression profiling using microarray hybridization. Immune-related gene expression signatures for CRC were identified from immune gene datasets, and an algorithmic predictive model was constructed for distinguishing CRC from controls. Model performance was characterized using an area under the receiver operating characteristic curve (ROC AUC). Functional categories for CRC-specific gene expression signatures were determined using gene set enrichment analyses. A Kaplan-Meier plotter survival analysis was also performed for CRC-specific immune genes in order to characterize the association between gene expression and CRC prognosis. The present study identified five CRC-specific immune genes [protein phosphatase 3 regulatory subunit Bα (PPP3R1), amyloid β precursor protein, cathepsin H, proteasome activator subunit 4 and DEAD-Box Helicase 3 X-Linked]. A predictive model based on this five-gene panel showed good discriminatory power (independent test set sensitivity, 83.3%; specificity, 94.7%, accuracy, 89.2%; ROC AUC, 0.96). The candidate genes were involved in pathways associated with 'adaptive immune responses', 'innate immune responses' and 'cytokine signaling'. The survival analysis found that a high level of PPP3R1 expression was associated with a poor CRC prognosis. The present study identified five CRC-specific immune genes that were potential diagnostic biomarkers for CRC. The biological function analysis indicated a close association between CRC pathogenesis and the immune system, and may reveal more information about the immunogenic and pathogenic mechanisms driving CRC in the future. Overall, the association between PPP3R1 expression and survival of patients with CRC revealed potential new targets for CRC immunotherapy.

SUBMITTER: Sun Z

PROVIDER: S-EPMC8157333 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:N6-methyladenosine (m6A) modification has been demonstrated to exhibit a crucial prognostic effect on colorectal cancer (CRC). Nonetheless, potential mechanism of m6A in survival rate and immunotherapeutic response remains unknown. Here we investigated the genes associated with m6A regulators and developed a risk score for predicting the overall survival (OS) of CRC patients. RNA-seq transcriptomic profiling data of COAD/READ samples were obtained from The Cancer Genome Atlas (TCGA) database. Absolute Shrinkage and Selection Operator (LASSO)- Cox regression analysis was conducted to identify the m6A-related gene expression signatures and the selected genes were inputted into stepwise regression to develop a prognostic risk score in TCGA, and its predictive performance of CRC survival was further validated in Gene Expression Omnibus (GEO) datasets. According to our results, the risk score comprising 18 m6A-related mRNAs was significantly associated with CRC survival in both TCGA and GEO datasets. And the stratified analysis also confirmed that high-risk score acted as a poor factor in different age, sex, T stage, and tumour, node, metastasis (TNM) stages. The m6A-related prognostic score in combination with clinical characteristics yielded time-dependent area under the receiver operating characteristic curve (AUCs) of 0.85 (95%CI: 0.79-0.91), 0.84 (95%CI: 0.79-0.90) and 0.80 (95%CI: 0.71-0.88) for the prediction of the 1-, 3-, 5-year OS of CRC in TCGA cohort. Furthermore, mutation of oncogenes occurred more frequently in the high-risk group and the composition of immune cells in tumour microenvironment (TME) was significantly distinct between the low- and high-risk groups. The low-risk group had a lower microsatellite instability (MSI) score, T-cell exclusion score and dysfunction score, implying that low-risk patients may have a better immunotherapy response than high-risk patients. In summary, a prognostic risk score derived from m6A-related gene expression signatures could serve as a potential prognostic predictor for CRC survival and indicator for predicting immunotherapy response in CRC patients.

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Immune-related gene expression signatures in colorectal cancer.

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