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Ferroptosis-related genes prognostic signature for pancreatic cancer and immune infiltration: potential biomarkers for predicting overall survival

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Abstract

Background

Pancreatic adenocarcinoma (PAAD) constitutes a lethal malignancy, notorious for its elevated mortality rates due to the difficulties in early diagnosis and rapid metastasis. The emerging paradigm of ferroptosis—an iron-catalyzed, regulated cell death distinguished by the accrual of lipid peroxides—has recently garnered scholarly focus. However, the expression landscape of ferroptosis-related genes (FRGs) in PAAD and their prognostic implications remain enigmatic.

Methods

We undertook a rigorous quantification of FRGs in PAAD samples, sourcing data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. These repositories also provided extensive metadata, encompassing mesenchymal stemness index (mRNAsi), genomic mutations, copy number variations (CNV), tumor mutational burden (TMB), and other clinical attributes. A predictive model was constructed utilizing Lasso regression analysis, and a co-expression study was executed to elucidate the complex interconnections between FRGs and other gene sets.

Results

Intriguingly, FRGs were substantially upregulated in the high-risk cohort, even in the absence of clinically manifest symptoms, emphasizing their utility as prognostic biomarkers. Gene set enrichment analysis (GSEA) revealed significant enrichment of immune and tumor-related pathways in this high-risk demographic. Striking heterogeneities in immune function and N6-methyladenosine (m6A) RNA modification were observed between the low- and high-risk groups. Our analysis further implicated a cohort of genes—including LINC01559, C11orf86, SERPINB5, DSG3, MSLN, EREG, FAM83A, CXCL5, LY6D, and PSCA—as cardinal mediators in PAAD pathogenesis. A convergence of our predictive model with an analysis of CNVs, single nucleotide polymorphisms (SNPs), and drug sensitivities, revealed an intricate relationship with the FRGs.

Conclusions

Our findings accentuate the salient role of FRGs as critical modulators in the pathogenesis and progression of PAAD. Importantly, our composite prognostic framework offers invaluable insights into PAAD clinical trajectory. Moreover, the complex crosstalk between FRGs and immune cell landscapes in the tumor microenvironment (TME) may elucidate prospective therapeutic strategies. The clinical translational utility of these insights, however, requires further in-depth empirical exploration. Accordingly, the FRG signature introduces a compelling new avenue for risk stratification and targeted therapeutic interventions in this devastating malignancy.

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Data availability

All the data can be obtained from the open-source website we provide, and the conclusion can be drawn through the analysis of the relevant software.

Abbreviations

PAAD:

Pancreatic adenocarcinoma

GO:

Gene Ontology

AUC:

Areas under the curve

MF:

Molecular functions

ICIs:

Immune checkpoint inhibitors

ROC:

Receiver-operating characteristics

GSEA:

Gene set enrichment analyses

KEGG:

Kyoto Encyclopedia of Genes and Genomes

TCGA:

The Cancer Genome Atlas

FRGs:

Ferroptosis-related genes

BP:

Biological processes

CC:

Cellular components

OS:

Overall survival

GEO:

Gene Expression Omnibus

DEGs:

Differentially expressed genes

ICRGs:

Immune checkpoint-related gene

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Acknowledgements

Thanks to the reviewers and editors for their sincere comments.

Funding

2022 Central Subsidy Funding Project for the Inheritance and Development of Chinese Medicine, Major Disease Key Specialist Construction—Department of Geriatrics (YWC2022ZYYSY001); Lu's Internal Medicine School Inheritance Studio Construction Project (lp2022-01).

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Author notes

  1. Lei Wang and Zixuan Wu contributed equally to this article as the first author.

  2. Chen Xu and Hang Yecontributed equally to this article as the corresponding author of this article.

Authors and Affiliations

  1. Affiliated Hospital of Shandong University of Chinese Medicine, Jinan, 250011, China

    Lei Wang

  2. Qilu Hospital (Qingdao), C Heeloo College of Medicine, Shandong University, 758 Hefei Road, Qingdao, 266035, Shandong, China

    Chen Xu

  3. Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China

    Chen Xu & Hang Ye

  4. Hunan University of Traditional Chinese Medicine, Changsha, 410208, Hunan, China

    Zixuan Wu & Hang Ye

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  1. Lei Wang
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Contributions

LW and ZW drafted and revised the manuscript. LW and ZW were in charge of data collection. HY and CX conceived and designed this article, in charge of syntax modification and revision of the manuscript. All the authors have read and agreed to the final version manuscript.

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Correspondence to Chen Xu or Hang Ye.

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Wang, L., Wu, Z., Xu, C. et al. Ferroptosis-related genes prognostic signature for pancreatic cancer and immune infiltration: potential biomarkers for predicting overall survival. J Cancer Res Clin Oncol 149, 18119–18134 (2023). https://doi.org/10.1007/s00432-023-05478-4

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