Molecular Subtypes Based on Cuproptosis-Related Genes and Tumor Microenvironment Infiltration Characterization in Colorectal Cancer

Abstract

Recent studies have demonstrated the biological significance of cuproptosis modification, a newly discovered programmed cell death, in tumor progression. Nonetheless, the potential role of cuproptosis-related genes (CRGs) in the immune landscape and tumor microenvironment (TME) formation of colorectal cancer (CRC) remains unknown. We comprehensively assessed cuproptosis modification patterns of 1339 CRC samples based on 27 CRGs and systematically analyzed the correlation of these patterns with TME. The CRG-score was constructed to quantify cuproptosis characteristics by LASSO and multivariate Cox regression methods, and its predictive capability was validated in an independent cohort. We identified three distinct cuproptosis modification patterns in CRC. The TME immune cell infiltration demonstrated immune heterogeneity among these three subtypes. Enrichment for multiple metabolism signatures was pronounced in cluster A. Cluster C was significantly correlated with the signaling pathways of immune activation-related, resulting in poor prognoses. Cluster B with mixed features possibly represents a transition phenotype or intratumoral heterogeneity. Then, based on constructed eight-gene CRG-score, we found that the signature could predict the disease-free survival of CRC patients, and the low CRG-score was related to increased neoantigen load, immunity activation, and microsatellite instability-high (MSI-H). Additionally, we observed significant correlations of the CRG-score with the cancer stem cell index and chemotherapeutic drug susceptibility. This study demonstrated that cuproptosis was correlated with tumor progression, prognosis, and TME. Our findings may improve the understanding of CRGs in TME infiltration characterization of CRC patients and contribute to guiding more effective clinical therapeutic strategies.

Experimental prognostic model integrating N6-methyladenosine-related programmed cell death genes in colorectal cancer

“… 10 , 41 It has been reported that m6A plays an increasingly important role in various physiological and pathological processes in various cancers, 42 including pancreatic cancer, 43 breast cancer, 44 and our published CRC study. 45 While the roles of various programmed cell death (PCD) modes in CRC prognosis have been explored in the literature, these models have primarily focused on individual modes of cell death, such as the apoptosis-related prognostic signature, 46 autophagy-related signature, 47 , 48 , 49 , 50 , 51 cuproptosis-related signature, 52 , 53 , 54 ferroptosis-related signature, 55 , 56 , 57 necroptosis-related signature, 58 , 59 and pyroptosis-related prognostic signature. 60 , 61 , 62 , 63 , 64 , 65 However, the interplay between m6A modification and PCD in CRC prognosis remains unexplored, representing a gap in the existing literature.…”

Cuproptosis-related risk score predicts prognosis and characterizes the tumor microenvironment in colon adenocarcinoma

“…Thanks to the large public database such as TCGA and GEO, we are able to access and analyze the transcriptome profiles of a variety of malignancies to gain a comprehensive understanding of genetic landscape, screen potential biomarkers, develop therapy strategies and predict patient outcome (68, 69). Several studies have described cuproptosis-related molecular patterns and the characterization of TME in colorectal cancer and found that cuproptosis patterns were closely associated with TME and served to predicted survival of patients with colorectal cancer (70)(71)(72)(73)(74). D. Hou, et al (75) developed a risk model of 11-cuproptosis-related lncRNAs to predict clinical and therapeutic implications of CRC patients.…”

Copper in colorectal cancer: From copper‐related mechanisms to clinical cancer therapies

“…Patients classified in the low‐risk group exhibiting stronger immunogenicity, higher immune scores, and a greater degree of microsatellite instability, suggesting a better response to immunotherapy. 50 , 145 , 155 , 156 , 157 , 158 , 159 Further investigation have highlighted the potential role of cuproptosis‐associated microRNAs and lncRNAs in CRC. For example, six cuproptosis‐associated miRNAs including hsa‐miR‐653, hsa‐miR‐216a, hsa‐miR‐3684, hsa‐miR‐4437, hsa‐miR‐641 and hsa‐miR‐552 were used to construct prognostic models.…”

“…Moreover, cuproptosis is closely linked to the tumour immune microenvironment. Patients classified in the low‐risk group exhibiting stronger immunogenicity, higher immune scores, and a greater degree of microsatellite instability, suggesting a better response to immunotherapy 50,145,155–159 . Further investigation have highlighted the potential role of cuproptosis‐associated microRNAs and lncRNAs in CRC.…”