A novel oxidative stress- and ferroptosis-related gene prognostic signature for distinguishing cold and hot tumors in colorectal cancer

Abstract

Oxidative stress and ferroptosis exhibit crosstalk in many types of human diseases, including malignant tumors. We aimed to develop an oxidative stress- and ferroptosis-related gene (OFRG) prognostic signature to predict the prognosis and therapeutic response in patients with colorectal cancer (CRC). Thirty-four insertion genes between oxidative stress-related genes and ferroptosis-related genes were identified as OFRGs. We then performed bioinformatics analysis of the expression profiles of 34 OFRGs and clinical information of patients obtained from multiple datasets. Patients with CRC were divided into three OFRG clusters, and differentially expressed genes (DEGs) between clusters were identified. OFRG clusters correlated with patient survival and immune cell infiltration. Prognosis-related DEGs in three clusters were used to calculate the risk score, and a prognostic signature was constructed according to the risk score. In this study, patients in the low-risk group had better prognosis, higher immune cell infiltration levels, and better responses to fluorouracil-based chemotherapy and immune checkpoint blockade therapy than high-risk patients; these results were successfully validated with multiple independent datasets. Thus, low-risk CRC could be defined as hot tumors and high-risk CRC could be defined as cold tumors. To further identify potential biomarkers for CRC, the expression levels of five signature genes in CRC and adjacent normal tissues were further verified via an in vitro experiment. In conclusion, we identified 34 OFRGs and constructed an OFRG-related prognostic signature, which showed excellent performance in predicting survival and therapeutic responses for patients with CRC. This could help to distinguish cold and hot tumors in CRC, and the results might be helpful for precise treatment protocols in clinical practice.

Integration of machine learning for developing a prognostic signature related to programmed cell death in colorectal cancer

“…32,33 Recent studies have attempted to use multi-gene panels in CRC but highlighted the need for more sophisticated, integrative approaches. 34,35 Our study aligns with the growing trend of utilizing machine learning in oncological prognostication. PCDS, as shown in our research, outperform traditional methods like multivariate Cox regression.…”

“…These models often fail to account for interactions and pathway crosstalk, thus limiting their prognostic utility 32,33 . Recent studies have attempted to use multi‐gene panels in CRC but highlighted the need for more sophisticated, integrative approaches 34,35 …”

Comparison of Machine Learning Methods for Predicting 3-Year Survival in Elderly Esophageal squamous cancer Patients Based on Oxidative Stress

“…At the same time, varying levels of oxidative stress can also alter phosphorylation levels, thereby regulating the malignancy and prognosis of malignant tumors 28 . Some researchers have proposed that oxidative stress may be associated with the expression of ferritin metabolism genes, thereby interfering with prognosis 29 . Animal model experiments have shown that in response to external stimuli, mice exhibit increased oxidative stress factors, leading to signi cant elevations in biochemical markers such as TBIL, lactate dehydrogenase (LDH), creatinine (CRE), and blood urea nitrogen (BUN), which can promote tumor initiation and progression 30 31 .…”

Feasibility and Tolerability of Anlotinib Plus PD-1 Blockades for Patients with Treatment-Refractory Metastatic Colorectal Cancer: A Retrospective Exploratory Study

“… 28 Converting these “cold tumors” into “hot tumors” by altering the tumor immune microenvironment presented a significant challenge in the field of immunotherapy for metastatic CRC. 29 A previous study concluded combination therapy as a potential solution to overcome this limitation, particularly through the administration of antiangiogenic drugs, which might potentially provide amazing survival benefits for patients with metastatic CRC. 30 Notably, antiangiogenic drugs not only conferred the ability to enhance the tumor immune microenvironment but also suppressed the development of tumor neovascularization, thereby achieving a synergistic action with immunotherapy.…”