Identification and Validation in a Novel Quantification System of Ferroptosis Patterns for the Prediction of Prognosis and Immunotherapy Response in Left- and Right-Sided Colon Cancer

Heng-Chun Zhang; Shen-Hui Deng; Ya-Nan Pi; Jun-Nan Guo; Hua Xi; Xin Shi; Xue-Fei Yang; Bo-Miao Zhang; Wei-Nan Xue; Bin-Bin Cui; Yan-Long Liu

doi:10.3389/fimmu.2022.855849

Identification and Validation in a Novel Quantification System of Ferroptosis Patterns for the Prediction of Prognosis and Immunotherapy Response in Left- and Right-Sided Colon Cancer

Front Immunol. 2022 Apr 4:13:855849. doi: 10.3389/fimmu.2022.855849. eCollection 2022.

Authors

Heng-Chun Zhang¹, Shen-Hui Deng², Ya-Nan Pi³, Jun-Nan Guo¹, Hua Xi¹, Xin Shi⁴, Xue-Fei Yang⁵, Bo-Miao Zhang¹, Wei-Nan Xue¹, Bin-Bin Cui¹, Yan-Long Liu¹

Affiliations

¹ Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, China.
² Department of Anesthesiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China.
³ Department of Gynecology, Harbin Medical University Cancer Hospital, Harbin, China.
⁴ Department of Rehabilitation Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
⁵ The First Department of Oncology, The First Affiliated Hospital of Harbin Medical University, Harbin, China.

Abstract

Background: This study aimed to establish a novel quantification system of ferroptosis patterns and comprehensively analyze the relationship between ferroptosis score (FS) and the immune cell infiltration (ICI) characterization, tumor mutation burden (TMB), prognosis, and therapeutic sensitivity in left-sided and right-sided colon cancers (LCCs and RCCs, respectively).

Methods: We comprehensively evaluated the ferroptosis patterns in 444 LCCs and RCCs based on 59 ferroptosis-related genes (FRGs). The FS was constructed to quantify ferroptosis patterns by using principal component analysis algorithms. Next, the prognostic value and therapeutic sensitivities were evaluated using multiple methods. Finally, we performed weighted gene co-expression network analysis (WGCNA) to identify the key FRGs. The IMvigor210 cohort, TCGA-COAD proteomics cohort, and Immunophenoscores were used to verify the predictive abilities of FS and the key FRGs.

Results: Two ferroptosis clusters were determined. Ferroptosis cluster B demonstrated a high degree of congenital ICI and stromal-related signal enrichment with a poor prognosis. The prognosis, response of targeted inhibitors, and immunotherapy were significantly different between high and low FS groups (HSG and LSG, respectively). HSG was characterized by high TMB and microsatellite instability-high subtype with poor prognosis. Meanwhile, LSG was more likely to benefit from immunotherapy. ALOX5 was identified as a key FRG based on FS. Patients with high protein levels of ALOX5 had poorer prognoses.

Conclusion: This work revealed that the evaluation of ferroptosis subtypes will contribute to gaining insight into the heterogeneity in LCCs and RCCs. The quantification for ferroptosis patterns played a non-negligible role in predicting ICI characterization, prognosis, and individualized immunotherapy strategies.

Keywords: colon cancer; ferroptosis; immunity; immunotherapy response; left-sided; prognosis; right-sided.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Biomarkers, Tumor / genetics
Colonic Neoplasms* / genetics
Colonic Neoplasms* / therapy
Ferroptosis* / genetics
Humans
Immunotherapy
Prognosis

Substances

Biomarkers, Tumor