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Article Open Access

Prognostic role and mutational characteristics of N6‑methyladenosine‑related genes in lung adenocarcinoma

  • Authors:
    • Jiahao Yang
    • Xiangpeng Chu
    • Zihao Chen
    • Yi Long
    • Jinghua Chen
  • View Affiliations / Copyright

    Affiliations: The First Clinical Medicine School of Guangdong Pharmaceutical University, Guangzhou, Guangdong 510080, P.R. China, Cancer Center, Guangzhou Twelfth People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510620, P.R. China, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, P.R. China
    Copyright: © Yang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 587
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    Published online on: October 14, 2025
       https://doi.org/10.3892/ol.2025.15333
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Abstract

 Lung adenocarcinoma (LUAD) is an invasive disease that originates from small airway epithelial cells or alveolar type II cells. Abnormal N6‑methyladenosine (m6A) RNA methylation serves a key role in the pathogenesis of human diseases, including cancer. RNA sequencing and somatic mutation data in the Genomic Data Commons (GDC) and The Cancer Genome Atlas (TCGA)‑LUAD were downloaded from University of California, Santa Cruz (UCSC) Xena database for a comprehensive analysis. m6A‑related genes were selected from the content of RNA m6A modification in cancer. m6A genes were further screened by comparing how m6A genes affected survival in normal and tumor groups and analyzing the relationship between m6A genes and LUAD. GDC LUAD data were downloaded from the UCSC Xena public database to analyze the differential expression levels of genes involved with m6A methylation regulators. Next, the mutations of m6A genes were analyzed and a univariate Cox regression analysis and the Kaplan‑Meier method were used to determine the relationship between their expression levels and overall survival time shown in TCGA database. Lastly, heterogeneous nuclear ribonucleoprotein C (HNRNPC), insulin‑like growth factor 2 mRNA binding protein (IGF2BP)1 and IGF2BP3 were selected for subsequent analysis. Enrichment analysis revealed that HNRNPC was mainly enriched in the ‘ribonucleoprotein complex biogenesis’ pathway, IGF2BP1 in the ‘mitotic cell cycle checkpoint’ pathway and IGF2BP3 in the ‘nuclear division’ pathway. The present study identified novel immune‑related prognostic markers for LUAD. Furthermore, the potential mechanisms of the prognostic markers in the regulation of LUAD etiology were investigated. The present study findings may provide novel insights into the treatment of patients with LUAD in the future.
View Figures

Figure 1

Mutation load in LUAD. TMB, tumor
mutation burden; LAML, acute myeloid leukemia; PCPG,
pheochromocytoma and paraganglioma; THCA, thyroid carcinoma; UVM,
uveal melanoma; TGCT, testicular germ cell tumors; THYM, thymoma;
KICH, kidney chromophobe; ACC, adrenocortical carcinoma; LGG, brain
lower grade glioma; MESO, mesothelioma; PRAD, prostate
adenocarcinoma; PAAD, pancreatic adenocarcinoma; BRCA, breast
invasive carcinoma; SARC, sarcoma; CHOL, cholangiocarcinoma; UCS,
uterine carcinosarcoma; GBM, glioblastoma; KIRC, kidney renal clear
cell carcinoma; KIRP, kidney renal papillary cell carcinoma; OV,
ovarian serous cystadenocarcinoma; UCEC, uterine corpus endometrial
carcinoma; LIHC, liver hepatocellular carcinoma; CESC, cervical
squamous cell carcinoma and endocervical adenocarcinoma; READ,
rectum adenocarcinoma; ESCA, esophageal carcinoma; HNSC, head and
neck squamous cell carcinoma; DLBC, lymphoid neoplasm diffuse large
B-cell lymphoma; STAD, stomach adenocarcinoma; COAD, colon
adenocarcinoma; LUAD, lung adenocarcinoma; BLCA, bladder urothelial
carcinoma; LUSC, lung squamous cell carcinoma; SKCM, skin cutaneous
melanoma.

Figure 2

Differential expression levels of m6A
genes between the tumor group and control group and the correlation
patterns. (A) The expression levels of all m6A genes, excluding
YTHDC1, YTHDC2, IGF2BP2 and YTHDF3, were significantly different
between the tumor and control groups. (B) Correlation analysis.
YTHDF3 had the strongest correlation with KIAA1429. **P<0.01 and
***P<0.001. m6A, N6-methyladenosine; YTHDC, YT521-B homology
domain-containing protein; IGF2BP2, insulin-like growth factor 2
mRNA binding protein 2; YTHDF3, YTHD-containing family protein 3;
KIAA1429, vir like m6A methyltransferase associated.

Figure 3

Somatic interaction between m6A genes
and the status of SNPs and highly mutated genomic regions. (A)
m6A-related mutated genes. (B) Stacked histogram of the proportion
of each sample. (C) Rainfall plot indicates highly mutated genomic
regions based on different SNP mutation types. (D) IGF2BP1 and
RBM15 had significant co-expression frequencies (P<0.05). m6A,
N6-methyladenosine; SNP, single nucleotide polymorphism; TMB, tumor
mutation burden; TCGA, The Cancer Genome Atlas; IGF2BP1,
insulin-like growth factor 2 mRNA binding protein 1; RBM15, RNA
binding motif protein 15.

Figure 4

Univariate Cox regression and
Kaplan-Meier analysis for the prognostic value of m6A RNA
methylation regulators in LUAD. (A) Univariate Cox regression
analysis showing that high expression of HNRNPC was associated with
poor prognosis in LUAD. (B) Univariate Cox regression analysis
showing that high expression of IGF2BP1 was associated with poor
prognosis in LUAD. (C) Univariate Cox regression analysis showing
that high expression of IGF2BP2 was associated with poor prognosis
in LUAD. (D) Univariate Cox regression analysis showing that high
expression of IGF2BP3 was associated with poor prognosis in LUAD.
(E) Univariate Cox regression analysis showing that high expression
of METTL5 was associated with poor prognosis in LUAD. m6A,
N6-methyladenosine; LUAD, lung adenocarcinoma; HNRNPC,
heterogeneous nuclear ribonucleoprotein C; IGF2BP, insulin-like
growth factor 2 mRNA binding protein; METTL5,
methyltransferase-like 5.

Figure 5

Nomogram construction for LUAD
prognosis prediction. Comparisons shown between the normal tissues
and stage I–IV groups using one-way ANOVA with Tukey's post hoc
test. (A) Differential expression analysis of HNRNPC across TNM
stages. (B) Differential expression analysis of IGF2BP1 across TNM
stages. (C) Differential expression analysis of IGF2BP3 across TNM
stages. LUAD, lung adenocarcinoma; HNRNPC, heterogeneous nuclear
ribonucleoprotein C; IGF2BP, insulin-like growth factor 2 mRNA
binding protein; TNM, tumor, lymph node metastasis.

Figure 6

m6A gene expression (HNRNPC, IGF2BP1
and IGF2BP3) in paracancerous and LUAD tissues was analyzed using
immunohistochemistry. Magnification, ×40 and ×100. m6A,
N6-methyladenosine; LUAD, lung adenocarcinoma; HNRNPC,
heterogeneous nuclear ribonucleoprotein C; IGF2BP, insulin-like
growth factor 2 mRNA binding protein.

Figure 7

Correlation analysis between m6A gene
expression and immune infiltration in LUAD. (A) Bone marrow
dendritic cells and regulatory T cells were significantly
positively and negatively correlated with HNRNPC, respectively. (B)
Cancer-associated fibroblasts, BMDCs and macrophages were
significantly positively correlated with IGF2BP1. (C) IGF2BP3 was
positively correlated with cancer-associated fibroblasts, BMDCs,
neutrophils, CD8+ T cells, and macrophages, but
negatively correlated with CD4+ T cells. (D)
Immunohistochemical detection of PD-L1, CD4, CD8 and FOXP3
expression in LUAD (scale bar, 200 and 50 µm) and paracancerous
tissues (scale bar, 200 and 50 µm). m6A, N6-methyladenosine; LUAD,
lung adenocarcinoma; HNRNPC, heterogeneous nuclear
ribonucleoprotein C; IGF2BP, insulin-like growth factor 2 mRNA
binding protein; BMDCs, bone marrow dendritic cells; PD-L1,
programmed cell death-ligand 1; FOXP3, Forkhead box P3; TPM,
transcripts per million.

Figure 8

Correlation between m6A gene
expression and T cell exhaustion in LUAD. (A) The correlation
between m6A gene expression and biomarkers of T cell exhaustion
(TNF, IL-2, IFN-γ and CTL) was analyzed based on previous research
datasets (PMID, 37284314 and 37284314). (B) Expression levels of
m6A genes in patients treated with anti-PD-1/PD-L1 based on a GEO
dataset (dataset no. GSE135222). (C) Expression levels of m6A genes
in patients treated with anti-PD-1/PD-L1 based on a GEO dataset
(dataset no. GSE126044). GEO, Gene Expression Omnibus; m6A,
N6-methyladenosine; LUAD, lung adenocarcinoma; HNRNPC,
heterogeneous nuclear ribonucleoprotein C; IGF2BP, insulin-like
growth factor 2 mRNA binding protein; PD-L1, programmed cell
death-ligand 1; PD-1, programmed cell death protein-1; PMID, PubMed
identifier; CTL, cytotoxic T lymphocytes.

Figure 9

Correlation between m6A gene
expression and the expression of immunomodulatory factors in LUAD.
HNRNPC and IGF2BP1 were negatively correlated with (A)
immunosuppressants, (B) immunostimulators and (C) MHC molecules,
whereas IGF2BP3 was negatively correlated with immunostimulants and
MHC molecules and positively correlated with immunosuppressants.
m6A, N6-methyladenosine; LUAD, lung adenocarcinoma; HNRNPC,
heterogeneous nuclear ribonucleoprotein C; IGF2BP, insulin-like
growth factor 2 mRNA binding protein; MHC, major histocompatibility
complex.

Figure 10

Enrichment analysis of the hub gene
and its related gene pathways. (A) HNRNPC was mainly enriched in
the ‘ribonucleoprotein complex biogenesis’ pathway. (B) IGF2BP1 was
mainly enriched in the ‘mitotic cell cycle checkpoint’ pathway. (C)
IGF2BP3 was mainly associated with the ‘nuclear division’ pathway.
HNRNPC, heterogeneous nuclear ribonucleoprotein C; IGF2BP,
insulin-like growth factor 2 mRNA binding protein; GO, Gene
Ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes.
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Copy and paste a formatted citation
Spandidos Publications style
Yang J, Chu X, Chen Z, Long Y and Chen J: Prognostic role and mutational characteristics of N6‑methyladenosine‑related genes in lung adenocarcinoma. Oncol Lett 30: 587, 2025.
APA
Yang, J., Chu, X., Chen, Z., Long, Y., & Chen, J. (2025). Prognostic role and mutational characteristics of N6‑methyladenosine‑related genes in lung adenocarcinoma. Oncology Letters, 30, 587. https://doi.org/10.3892/ol.2025.15333
MLA
Yang, J., Chu, X., Chen, Z., Long, Y., Chen, J."Prognostic role and mutational characteristics of N6‑methyladenosine‑related genes in lung adenocarcinoma". Oncology Letters 30.6 (2025): 587.
Chicago
Yang, J., Chu, X., Chen, Z., Long, Y., Chen, J."Prognostic role and mutational characteristics of N6‑methyladenosine‑related genes in lung adenocarcinoma". Oncology Letters 30, no. 6 (2025): 587. https://doi.org/10.3892/ol.2025.15333
Copy and paste a formatted citation
x
Spandidos Publications style
Yang J, Chu X, Chen Z, Long Y and Chen J: Prognostic role and mutational characteristics of N6‑methyladenosine‑related genes in lung adenocarcinoma. Oncol Lett 30: 587, 2025.
APA
Yang, J., Chu, X., Chen, Z., Long, Y., & Chen, J. (2025). Prognostic role and mutational characteristics of N6‑methyladenosine‑related genes in lung adenocarcinoma. Oncology Letters, 30, 587. https://doi.org/10.3892/ol.2025.15333
MLA
Yang, J., Chu, X., Chen, Z., Long, Y., Chen, J."Prognostic role and mutational characteristics of N6‑methyladenosine‑related genes in lung adenocarcinoma". Oncology Letters 30.6 (2025): 587.
Chicago
Yang, J., Chu, X., Chen, Z., Long, Y., Chen, J."Prognostic role and mutational characteristics of N6‑methyladenosine‑related genes in lung adenocarcinoma". Oncology Letters 30, no. 6 (2025): 587. https://doi.org/10.3892/ol.2025.15333
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