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Immune-related gene methylation prognostic instrument for stratification and targeted treatment of ovarian cancer patients toward advanced 3PM approach

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Abstract

Background

DNA methylation is an important mechanism in epigenetics, which can change the transcription ability of genes and is closely related to the pathogenesis of ovarian cancer (OC). We hypothesize that DNA methylation is significantly different in OCs compared to controls. Specific DNA methylation status can be used as a biomarker of OC, and targeted drugs targeting these methylation patterns and DNA methyltransferase may have better therapeutic effects. Studying the key DNA methylation sites of immune-related genes (IRGs) in OC patients and studying the effects of these methylation sites on the immune microenvironment may provide a new method for further exploring the pathogenesis of OC, realizing early detection and effective monitoring of OC, identifying effective biomarkers of DNA methylation subtypes and drug targets, improving the efficacy of targeted drugs or overcoming drug resistance, and better applying it to predictive diagnosis, prevention, and personalized medicine (PPPM; 3PM) of OC.

Method

Hypermethylated subtypes (cluster 1) and hypomethylated subtypes (cluster 2) were established in OCs based on the abundance of different methylation sites in IRGs. The differences in immune score, immune checkpoints, immune cells, and overall survival were analyzed between different methylation subtypes in OC samples. The significant pathways, gene ontology (GO), and protein-protein interaction (PPI) network of the identified methylation sites in IRGs were enriched. In addition, the immune-related methylation signature was constructed with multiple regression analysis. A methylation site model based on IRGs was constructed and verified.

Results

A total of 120 IRGs with 142 differentially methylated sites (DMSs) were identified. The DMSs were clustered into a high-level methylation group (cluster 1) and a low-level methylation group (cluster 2). The significant pathways and GO analysis showed many immune-related and cancer-associated enrichments. A methylation site signature based on IRGs was constructed, including RORC|cg25112191, S100A13|cg14467840, TNF|cg04425624, RLN2|cg03679581, and IL1RL2|cg22797169. The methylation sites of all five genes showed hypomethylation in OC, and there were statistically significant differences among RORC|cg25112191, S100A13|cg14467840, and TNF|cg04425624 (p < 0.05). This prognostic model based on low-level methylation and high-level methylation groups was significantly linked to the immune microenvironment as well as overall survival in OC.

Conclusions

This study provided different methylation subtypes for OC patients according to the methylation sites of IRGs. In addition, it helps establish a relationship between methylation and the immune microenvironment, which showed specific differences in biological signaling pathways, genomic changes, and immune mechanisms within the two subgroups. These data provide ones to deeply understand the mechanism of immune-related methylation genes on the occurrence and development of OC. The methylation-site signature is also to establish new possibilities for OC therapy. These data are a precious resource for stratification and targeted treatment of OC patients toward an advanced 3PM approach.

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Data availability

All data and materials are provided in this article and supplemental materials, which can be available publicly.

Code availability

All protein and gene accession codes can be available in the Swiss-Prot and Genbank databases.

Abbreviations

ADAR1:

Adenosine deaminase 1

BPs:

Biological processes

CTC:

Circulating tumor cells

cfDNA:

Cell-free DNA

ctDNA:

Circulating tumor DNA

DCs:

Dendritic cells

DMAPT:

Dimethylaminoporphanolide

DMDGs:

Differential methylation-driven genes

DMSs:

Differentially methylated sites

DNMTs:

DNA methyltransferases

DNMTi:

DNA methyltransferase inhibitors

GO:

Gene ontology terms

Hcy:

Homocysteine

ICI:

Immune checkpoint inhibitor

IL-1RL2:

Interleukin-1 receptor-like 2

IRGs:

Immune-related genes

KEGG:

Kyoto Encyclopedia of Genes and Genomes

MDGs:

Methylation-driven genes

MESA:

Multimodal epigenetic sequencing analysis

MSP:

Methylation‑specific polymerase chain reaction

OC:

Ovarian cancer

OS:

Overall survival

PACA:

Pancreatic cancer

PPI:

Protein-protein interaction

Sat2:

Satellite near the central point 2

Satα:

Satellite near the central point α

ssGSEA:

Single-sample Gene Set Enrichment Analysis

TCGA:

The Cancer Genome Atlas

TCRs:

T-cell antigen receptors

TIME:

Tumor immune microenvironment

TME:

Tumor microenvironment

Tregs:

T-cell regulatory

UCEC:

Uterus corpus endometrial cancer

Aza-CdR:

5-Aza-2′-deoxycytidine

5mC:

5-Methylcytosine

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Acknowledgements

The authors acknowledge The Cancer Genome Atlas (TCGA) project organizers as well as all study participants to provide the publicly available TCGA RNA-seq data and clinical data.

Funding

This work was supported by the Shandong Provincial Taishan Scholar Engineering Project Special Funds (to X.Z.), the Shandong Provincial Natural Science Foundation (ZR2021MH156; ZR2022QH112; ZR2020LZL012), the Shandong First Medical University Talent Introduction Funds (to X.Z.), the Shandong First Medical University High-level Scientific Research Achievement Cultivation Funding Program (to X.Z.), the China National Nature Scientific Funds (82203592), the CSCO-CSPC Cancer Research Fund Project (Y-SY2021QN-0152), the Clinical Research Fund Project of Shandong Medical Association (YXH2022ZX02149), and the Beijing Science and Technology Innovation Medical Development Foundation (No. KC2021-JX-0186–138).

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  1. Wenshuang Jia and Na Li equally contributed to this work.

Authors and Affiliations

  1. Medical Science and Technology Innovation Center, Shandong Provincial Key Medical and Health Laboratory of Ovarian Cancer Multiomics, & Shandong Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, 440 Jiyan Road, Jinan, Shandong, 250117, People’s Republic of China

    Wenshuang Jia, Na Li, Xiaoxia Gong, Serge Yannick Ouedraogo, Yan Wang, Junkai Zhao & Xianquan Zhan

  2. Department of Pathology, Shandong Cancer Hospital and Institute, Shandong First Medical University, 440 Jiyan Road, Jinan, Shandong, 250117, People’s Republic of China

    Jingjing Wang

  3. Department of Gynecological Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, 440 Jiyan Road, Jinan, 250117, People’s Republic of China

    Yan Wang & Liang Chen

  4. Department of Pathology, University of Malta, Msida, Malta

    Godfrey Grech

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  1. Wenshuang Jia
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Contributions

W.J. analyzed partial data, performed methylation experiments, and wrote the manuscript draft. N.L. conceived the concept, analyzed data, and wrote the manuscript. J.W., X.G., Y.W., and J.Z. analyzed partial data. S.Y.O and G.G. reviewed and critically revised the manuscript. L.C. supervised the data and edited the manuscript. X.Z. conceived the concept, coordinated and critically revised the manuscript, and was responsible for the corresponding works. All authors approved the final manuscript.

Corresponding authors

Correspondence to Liang Chen or Xianquan Zhan.

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Ethical approval

All investigations conformed to the principles outlined in the Declaration of Helsinki, and the research protocol was approved by the Medical Ethics Committee of Shandong First Medical University, China. All the patients were informed about the purposes of the study and consequently have signed their “consent of the patient.”. It includes the following four aspects:

- Approval of the research protocol by an Institutional Reviewer Board: Yes.

- Informed Consent: Yes.

- Registry and the Registration No. of the study: 202105200158.

- Animal Studies: N/A.

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Jia, W., Li, N., Wang, J. et al. Immune-related gene methylation prognostic instrument for stratification and targeted treatment of ovarian cancer patients toward advanced 3PM approach. EPMA Journal (2024). https://doi.org/10.1007/s13167-024-00359-3

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