An Original Ferroptosis-Related Gene Signature Effectively Predicts the Prognosis and Clinical Status for Colorectal Cancer Patients

Abstract

BackgroundColorectal cancer (CRC) is one of the most common malignant tumors in the world. Ferroptosis is a newly defined form of cell death, distinguished by different morphology, biochemistry, and genetics, and involved in CRC progression and treatment. This study aims to establish a predictive model to elucidate the relationship between ferroptosis and prognosis of CRC patients, to explore the potential value of ferroptosis in therapeutic options.MethodsThe ferroptosis-related genes were obtained from the GeneCards and FerrDb websites. The limma R package was used to screen the differential ferroptosis-related genes (DEGs) in CRC from The Cancer Genome Atlas (TCGA) dataset. The least absolute shrinkage and selection operator (LASSO) and multivariate Cox regressions were to establish the 10-gene prognostic signature. The survival and receiver operating characteristic (ROC) curves were illustrated to evaluate the predictive effect of the signature. Besides, independent prognostic factors, downstream functional enrichment, drug sensitivity, somatic mutation status, and immune feature were analyzed. Moreover, all these conclusions were verified by using multiple datasets in International Cancer Genome Consortium (ICGC) and Gene Expression Omnibus (GEO).ResultsTen ferroptosis-related gene signature (TFAP2C, SLC39A8, NOS2, HAMP, GDF15, FDFT1, CDKN2A, ALOX12, AKR1C1, ATP6V1G2) was established to predict the prognosis of CRC patients by Lasso cox analysis, demonstrating a good performance on Receiver operating characteristic (ROC) and Kaplan–Meier (K–M) analyses. The CRC patients in the high- or low-risk group showed significantly different fractions of immune cells, such as macrophage cells and CD8+ T cells. Drug sensitivity and somatic mutation status like TP53 were also closely associated with the risk scores.ConclusionsIn this study, we identified a novel ferroptosis-related 10-gene signature, which could effectively predict the prognosis and survival time of CRC patients, and provide meaningful clinical implications for targeted therapy or immunotherapy. Targeting ferroptosis is a good therapeutic option for CRC patients. Further studies are needed to reveal the underlying mechanisms of ferroptosis in CRC.

Bioinformatics Analysis Identifies Potential Ferroptosis Key Genes in the Pathogenesis of Pulmonary Fibrosis

“…Excessive nitric oxide production may contribute to fibrosis development ( Jang et al, 2004 ). GDF15 is an endocrine hormone and a member of the transforming growth factor β superfamily that promotes ferroptosis in tumor cells ( Shao et al, 2021 ). Zhang ( Zhang et al, 2019 ) et al reported that GDF15 is a secreted protein of epithelial origin and may be a useful biomarker of epithelial stress since its increased expression associates with a poorer prognosis in IPF patients, which is consistent with the findings of the present bioinformatics analyses in this study.…”

Prognostic and Predictive Models for Left- and Right- Colorectal Cancer Patients: A Bioinformatics Analysis Based on Ferroptosis-Related Genes

“…It was initially shown to be a major player in the antitumor component of the immune response. However, recent data suggest that high expression of NOS2 in cancer cells often predicts poor outcomes, such as high expression in breast cancer (21), lung cancer (22),gliomas (23) and colon cancer (24).Shao et al (25)also found that NOS2 was significantly up-regulated in colon cancer in their study on ferroptosis-related genes predicting the prognosis of colon cancer patients. Similarly, in this experiment, we also found that NOS2 was significantly overexpressed in colon cancer, but there was no significant difference in expression between leftsided and right-sided colon cancers.…”

Construction and Clinical Translation of Causal Pan-Cancer Gene Score Across Cancer Types

“…As expected, the association between all 12 CAPER genes and cancers have been demonstrated using a series of basic experimental and population-based studies. For example, ATP6V1G2 is a ferroptosis-related gene that plays a primary role in metabolism and oxidative stress and is defined as a colorectal cancer prognosis biomarker ( Huang et al, 2021 ; Shao et al, 2021 ). DDX39B is involved in the regulation of pre-mRNA splicing, nuclear export of mRNAs, and pre-ribosomal RNA translation, and may promote the genesis, development, and metastasis of multiple cancer types by regulating cell proliferation ( Awasthi et al, 2018 ; Gu et al, 2020 ; Xu et al, 2020 ; He et al, 2021 ).…”