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Gene Signatures and Cancer-Immune Phenotypes Based on m⁶A Regulators in Breast Cancer.

ABSTRACT: The N⁶-methyladenosine (m⁶A) has been considered as a new layer of epitranscriptomic regulation on mRNA processing, stability, and translation. However, potential roles of m⁶A RNA methylation modification in tumor immune microenvironment (TIME) of breast cancer are yet fully understood. In this study, we comprehensively evaluated the genetic variations and transcript expressions of 15 m⁶A regulators in 1,079 breast cancer samples from the Cancer Genome Atlas (TCGA) database. We validated major regulators had significantly differential mRNA and protein expression in tumor tissue compared to normal tissues from 39 pairs of clinical breast cancer samples with different molecular subtypes, and especially high expression of m⁶A readers YTHDF1 and YTHDF3 predicted poor survival. Two clusters of breast cancer patients identified by the 15 m⁶A regulators' pattern showed distinct overall survival, immune activation status, and immune cell infiltration, and clinical samples confirmed the diversity of lymphocytic infiltration. The profiles of these two clusters accorded with that of two classical cancer-immune phenotypes, immune-excluded and immune-inflamed phenotypes, it suggested that m⁶A regulators-based patterns might serve as crucial mediators of TIME in breast cancer. Moreover, the m⁶A phenotype-related gene signatures could also be survival predictor in breast cancer. Therefore, comprehensive evaluation of tumor m⁶A modification pattern will contribute to enhance our understanding of the characterization of immune cell infiltration in the tumor microenvironment and promote the responsiveness of breast cancer to immunotherapy.

SUBMITTER: Zhao G

PROVIDER: S-EPMC8600443 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The significance of N6-methyladenosine (m6A) RNA modifications in the progression of breast cancer (BC) has been recognised. However, their potential role and mechanism of action in the tumour microenvironment (TME) and immune response has not been demonstrated. Thus, the role of m6A regulators and their downstream target gene components in BC remain to be explored. In this study, we used a series of bioinformatics methods and experiments to conduct exploratory research on the possible role of m6A regulators in BC. First, two regulatory modes of immune activation and inactivation were determined by tumour classification. The TME, immune cell infiltration, and gene set variation analysis results confirmed the reliability of this pattern. The prognostic model of the m6A regulator was established by the least absolute shrinkage and selection operator and univariate and multivariate Cox analyses, with the two regulators most closely related to survival verified by real-time quantitative reverse transcription polymerase chain reaction. Next, the prognostic m6A regulator identified in the model was crossed with the differential copy number of variant genes in invasive BC (IBC), and it was determined that YTHDF1 was a hub regulator. Subsequently, single-cell analysis revealed the expression patterns of m6A regulators in different IBC cell populations and found that YTHDF1 had significantly higher expression in immune-related IBC cells. Therefore, we selected the intersection of the BC differential expression gene set and the differential expression gene set of a cell line with knocked-down YTHDF1 in literature to identify downstream target genes of YTHDF1, in which we found IFI6, EIR, and SPTBN1. A polymerase chain reaction was conducted to verify the results. Finally, we confirmed the role of YTHDF1 as a potential prognostic biomarker through pan-cancer analysis. Furthermore, our findings revealed that YTHDF1 can serve as a new molecular marker for BC immunotherapy.

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Gene Signatures and Cancer-Immune Phenotypes Based on m⁶A Regulators in Breast Cancer.

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Dataset Information

Gene Signatures and Cancer-Immune Phenotypes Based on m6A Regulators in Breast Cancer.

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OmicsDI is part of the ELIXIR infrastructure

Tweets

Gene Signatures and Cancer-Immune Phenotypes Based on m⁶A Regulators in Breast Cancer.