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Characterization of m6A methylation modifications and tumor microenvironment infiltration in thyroid cancer

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Abstract

Background

Thyroid cancer (TC) is the most common endocrine malignancy worldwide, and immunotherapy is a new cancer treatment that stimulates and enhances the natural ability of the immune system to fight cancer cells. The role of RNA N6-methyladenosine (m6A) related genes in these challenges has recently become a research hotspot, but he potential role of m6A modifications in tumor microenvironment (TME) cell infiltration remains unknown.

Purpose

There is growing evidence that m6A plays a critical role in the regulation of gene expression by participating in important biological processes. A comprehensive analysis of the m6A regulator-mediated infiltration characteristics of the TME will help advance the understanding of immune regulation in thyroid tumors.

Methods

This study assessed m6A modification modes in 510 thyroid cancer samples from the Cancer Genome Atlas (TCGA) databases according to a comprehensive set of 24 m6A regulators. In this study, we analyzed the biological characteristics and m6A methylation modification patterns. Based on this, we constructed m6A signatures and analyzed m6A modification features in tumor somatic mutations and TCGA molecular subtypes.

Results

These modification modes were systematically linked to TME cell infiltration signatures. m6A modification patterns were comprehensively assessed and correlated with immune cell infiltration features in the TME. An unsupervised clustering approach was applied and three distinct m6A modification subtypes and three m6A-associated gene subtypes were identified. Additionally, three distinct m6A methylation modification modes were identified in the thyroid cancer samples. The TME profiles of the identified genetic subtypes were strongly congruent with the immuno-heat and immuno-cold phenotypes.

Conclusions

The results revealed that m6A modifications play an integral role in the diversity and complexity of thyroid carcinomas. Evaluating the m6A modification patterns of individual tumors will create more efficient immunotherapeutic strategies. A comprehensive analysis of the role of TME in thyroid cancer provides a research idea for studying the effect of m6A epigenetics on thyroid tumors and their immune microenvironment.

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Availability of data and materials

The datasets analyzed during the current study are available in the TCGA repository (https:// portal. gdc. cancer. gov) and UCSC Xena (https://xena.ucsc.edu/) database.

Abbreviations

TCGA:

The Cancer Genome Atlas

TC:

Thyroid cancer

PTC:

Papillary thyroid carcinoma

m6A:

RNA N6-methyladenosine

TME:

Tumor microenvironment

ZC3H13:

Zinc finger CCCH-type containing 13

WTAP:

Wilms' tumor 1 associated protein

VIRMA:

Vir like m6A methyltransferase associated

ALKBH5:

AlkB homolog 5, RNA demethylase

RBM15:

RNA binding motif protein 15

METTL3/14/16:

Methyltransferase 3/14/16

RBM15B:

RNA binding motif protein 15B

LRPPRC:

Leucine rich pentatricopeptide repeat containing

FTO:

Fat mass and obesity-associated gene

FMR1:

Fragile X messenger ribonucleoprotein 1

RBMX:

RNA binding motif protein X-linked

HNRNPC:

Heterogeneous nuclear ribonucleoprotein C

EIF3A:

Eukaryotic translation initiation factor 3 subunit A

YTHDF1/2/3:

YTH N6-methyladenosine RNA binding protein 1/2/3

YTHDC1/2:

YTH domain containing 1/2

HNRNPA2B1:

Heterogeneous nuclear ribonucleoprotein A2/B1

IGFBP1:

Insulin like growth factor binding protein 1/2/3, /2/3

ssGSEA:

Single-Sample Gene Set Enrichment Analysis

CNV:

Copy number variation

GDC:

Genomic Data Commons

DEGs:

Differential expression genes

TCIA:

The Cancer Tumor Immune Atlas

GSVA:

Gene Set Variation Analysis

UCSC:

University of California, Santa Cruz

PD-1:

Programmed death-1

KEGG:

Kyoto Encyclopedia of Gene and Genomes

CTLA4:

Cytotoxic T-lymphocyte associated protein 4

GO:

Gene Ontology

CXCR4:

C-X-C motif chemokine receptor 4

IPS:

Immunophenoscore

SOX10:

SRY-box transcription factor 10

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Acknowledgements

We are grateful to the Center for Translational Medicine of the First Affiliated Hospital of Zhengzhou University for its support in providing analytical tools. We would also like to thank the English editors of Editage (www.editage.cn).

Funding

This work was supported by a grant from Thermal Ablation of Thyroid Nodules International Joint Laboratory (Henan Province) (YUKEWAI【2016】NO.11).

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Authors and Affiliations

  1. Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China

    Fei-Hong Ji, Zhen yang & Xin-Guang Qiu

  2. AMITA Health Saint Joseph Hospital Chicago, 2900 N. Lake Shore Drive, Chicago, IL, 60657, USA

    Chenyu Sun

  3. College of Osteopathic Medicine, Kansas City University, 1750 Independence Ave, Kansas City, MO, 64106, USA

    Scott Lowe

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Contributions

FHJ and ZY contributed to the conception, study design, and collected data, CS and SL analyzed the data and drafted the manuscript. And XGQ were responsible for revising and correcting the manuscript. All authors reviewed and approved the manuscript.

Corresponding author

Correspondence to Xin-Guang Qiu.

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The authors declare no competing interests.

Ethics approval

The study was conducted in accordance with the Declaration of Helsinki Principles, approval was obtained from the Ethics Committee of the First Affiliated Hospital of Zhengzhou University (ethical review number: 2021-KY-0202).

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Informed consent was obtained from all patients.

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Ji, FH., yang, Z., Sun, C. et al. Characterization of m6A methylation modifications and tumor microenvironment infiltration in thyroid cancer. Clin Transl Oncol 25, 269–282 (2023). https://doi.org/10.1007/s12094-022-02940-6

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