Integrative analysis of multi-omics data for discovery of ferroptosis-related gene signature predicting immune activity in neuroblastoma

Jiajian Hu; Fengju Song; Wenjuan Kang; Fantong Xia; Zi'an Song; Yangyang Wang; Jie Li; Qiang Zhao

doi:10.3389/fphar.2023.1162563

Integrative analysis of multi-omics data for discovery of ferroptosis-related gene signature predicting immune activity in neuroblastoma

Front Pharmacol. 2023 Jul 13:14:1162563. doi: 10.3389/fphar.2023.1162563. eCollection 2023.

Authors

Jiajian Hu¹, Fengju Song², Wenjuan Kang², Fantong Xia¹, Zi'an Song¹, Yangyang Wang¹, Jie Li¹, Qiang Zhao¹

Affiliations

¹ Tianjin Key Laboratory of Cancer Prevention and Therapy, Department of Pediatric Oncology, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
² Key Laboratory of Molecular Cancer Epidemiology, Department of Epidemiology and Biostatistics, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.

Abstract

Immunotherapy for neuroblastoma remains unsatisfactory due to heterogeneity and weak immunogenicity. Exploring powerful signatures for the evaluation of immunotherapy outcomes remain the primary purpose. We constructed a ferroptosis-related gene (FRG) signature by least absolute shrinkage and selection operator and Cox regression, identified 10 independent prognostic FRGs in a training cohort (GSE62564), and then verified them in an external validation cohort (TCGA). Associated with clinical factors, the signature accurately predicts overall survival of 3, 5, and 10 years. An independent prognostic nomogram, which included FRG risk, age, stage of the International Neuroblastoma Staging System, and an MYCN status, was constructed. The area under the curves showed satisfactory prognostic predicting performance. Through bulk RNA-seq and proteomics data, we revealed the relationship between hub genes and the key onco-promoter MYCN gene and then validated the results in MYCN-amplified and MYCN-non-amplified cell lines with qRT-PCR. The FRG signature significantly divided patients into high- and low-risk groups, and the differentially expressed genes between the two groups were enriched in immune actions, autophagy, and carcinogenesis behaviors. The low-risk group embodied higher positive immune component infiltration and a higher expression of immune checkpoints with a more favorable immune cytolytic activity (CYT). We verified the predictive power of this signature with data from melanoma patients undergoing immunotherapy, and the predictive power was satisfactory. Gene mutations were closely related to the signature and prognosis. AURKA and PRKAA2 were revealed to be nodal hub FRGs in the signature, and both were shown to have significantly different expressions between the INSS stage IV and other stages after immunohistochemical validation. With single-cell RNA-seq analysis, we found that genes related to T cells were enriched in TNFA signaling and interferon-γ hallmark. In conclusion, we constructed a ferroptosis-related gene signature that can predict the outcomes and work in evaluating the effects of immunotherapy.

Keywords: ferroptosis; gene; immune; neuroblastoma; survival.

Grants and funding

This work was supported by the National Key R&D Program of China (2018YFC1313000, 2018YFC1313001, and 2018YFC1313004) and the National Key R&D Program of China (2021YFC2500400 and 2021YFC2500404).