Combined signature of N7-methylguanosine regulators with their related genes and the tumor microenvironment: a prognostic and therapeutic biomarker for breast cancer

Tingjun Li; Zhishan Chen; Zhitang Wang; Jingyu Lu; Debo Chen

doi:10.3389/fimmu.2023.1260195

Combined signature of N7-methylguanosine regulators with their related genes and the tumor microenvironment: a prognostic and therapeutic biomarker for breast cancer

Front Immunol. 2023 Oct 5:14:1260195. doi: 10.3389/fimmu.2023.1260195. eCollection 2023.

Authors

Tingjun Li^{1

2}, Zhishan Chen³, Zhitang Wang^{1

2}, Jingyu Lu^{1

4}, Debo Chen^{1

2}

Affiliations

¹ The School of Clinical Medicine, Fujian Medical University, Fuzhou, China.
² Department of Breast Surgery, Quanzhou First Hospital of Fujian Medical University, Quanzhou, China.
³ Department of Breast and Thyroid Surgery, Nan'an Hospital, Quanzhou, China.
⁴ Department of Breast Surgery, The Affiliated Hospital of Putian University, Putian, China.

Abstract

Background: Identifying predictive markers for breast cancer (BC) prognosis and immunotherapeutic responses remains challenging. Recent findings indicate that N⁷-methylguanosine (m7G) modification and the tumor microenvironment (TME) are critical for BC tumorigenesis and metastasis, suggesting that integrating m7G modifications and TME cell characteristics could improve the predictive accuracy for prognosis and immunotherapeutic responses.

Methods: We utilized bulk RNA-sequencing data from The Cancer Genome Atlas Breast Cancer Cohort and the GSE42568 and GSE146558 datasets to identify BC-specific m7G-modification regulators and associated genes. We used multiple m7G databases and RNA interference to validate the relationships between BC-specific m7G-modification regulators (METTL1 and WDR4) and related genes. Single-cell RNA-sequencing data from GSE176078 confirmed the association between m7G modifications and TME cells. We constructed an m7G-TME classifier, validated the results using an independent BC cohort (GSE20685; n = 327), investigated the clinical significance of BC-specific m7G-modifying regulators by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis, and performed tissue-microarray assays on 192 BC samples.

Results: Immunohistochemistry and RT-qPCR results indicated that METTL1 and WDR4 overexpression in BC correlated with poor patient prognosis. Moreover, single-cell analysis revealed relationships between m7G modification and TME cells, indicating their potential as indicators of BC prognosis and treatment responses. The m7G-TME classifier enabled patient subgrouping and revealed significantly better survival and treatment responses in the m7G^low+TME^high group. Significant differences in tumor biological functions and immunophenotypes occurred among the different subgroups.

Conclusions: The m7G-TME classifier offers a promising tool for predicting prognosis and immunotherapeutic responses in BC, which could support personalized therapeutic strategies.

Keywords: N 7 -methylguanosine modification; breast cancer; immunotherapy; prognosis; tumor microenvironment.

Publication types

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

MeSH terms

Biomarkers
Breast Neoplasms* / diagnosis
Breast Neoplasms* / genetics
Breast Neoplasms* / therapy
Female
GTP-Binding Proteins
Humans
Prognosis
RNA
Tumor Microenvironment / genetics

Substances

8-methylguanosine
Biomarkers
RNA
WDR4 protein, human
GTP-Binding Proteins

Grants and funding

The authors declare financial support was received for the research, authorship, and/or publication of this article. The Medical Innovation Project Foundation of Fujian Province, PRC (grant number 2021CXA045), Science and Technology Innovation Joint Fund Project of Fujian Province (grant number 2019Y9049), Science and Technology Project of Quanzhou (grant number 2020C047R), and Special Fund for Clinical Research of the Wu Jieping Medical Foundation (grant number 320.6750.2021-10-60) provided financial support for this study.