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Background <p>While DNA methylation profiling from peripheral blood mononuclear cells (PBMCs) has demonstrated utility in cancer risk prediction, notably for non-small cell lung cancer (NSCLC), its prognostic value for survival stratification in Chinese lung adenocarcinoma (LUAD) patients remains unestablished. This study addresses whether PBMC-derived methylation signatures can discriminate clinical outcomes in EGFR-mutation LUAD subgroups.</p> Methods <p>We performed genome-wide methylation analysis of PBMCs from LUAD patients using the Infinium Methylation EPIC 850&#xa0;K array. Clinical characteristics were associated with overall survival (OS) through Cox regression. Prognostic differentially methylated positions (DMPs) were identified via Lasso regression, followed by the construction of risk-score models. Functional enrichment (KEGG/GO) and tissue microarray-based immunohistochemistry (IHC) for FKBP4 expression (<i>n</i> = 90 LUAD samples) were conducted. Analyses were conducted in R 4.4.1 with curated Bioconductor packages.</p> Results <p>In the retrospective cohort of 174 Chinese LUAD patients (April 2014–September 2019), PBMC analysis of 128 cases revealed 12 hypomethylated DMPs were associated with OS. EGFR-mutant patients (<i>n</i> = 66) showed 325 significant DMPs (|Δ<i>β</i>|≥ 0.06, <i>P</i> ≤ 0.01), with four DMPs (cg05802998, cg19313959, cg00685115, cg15224444) independently predicting OS. The cg19313959 located in the TSS1500 region of FKBP4 gene (Δ<i>β</i> = 0.21) demonstrated the strongest methylation shift. Reduced FKBP4 protein expression was associated with improved survival (HR = 0.42, 95%CI 0.24–0.72). In EGFR-wildtype patients (<i>n</i> = 51), three prognostic DMPs emerged from 2,531 candidates. EGFR mutation-specific prognostic scoring models were established successfully, while pathway analyses revealed divergent biological processes between EGFR subgroups.</p> Conclusion <p>In this epigenome-wide study based on PBMCs in Chinese patients with LUAD, methylation signatures dependent on EGFR mutations and predictive of survival were identified.</p>

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Peripheral blood mononuclear cell DNA methylation biomarkers for prognostic stratification in Chinese lung adenocarcinoma: a genome-wide epigenetic profiling study

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月27日

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  • Peng Li,
  • Cuicui Zhang,
  • Sen Yang,
  • Yingxi Wu,
  • Haiyang Chen,
  • Shuxiang Ma,
  • Yufeng Wu,
  • Zhen He,
  • Lili Wang,
  • Yang Liu,
  • Qiming Wang

摘要

Background

While DNA methylation profiling from peripheral blood mononuclear cells (PBMCs) has demonstrated utility in cancer risk prediction, notably for non-small cell lung cancer (NSCLC), its prognostic value for survival stratification in Chinese lung adenocarcinoma (LUAD) patients remains unestablished. This study addresses whether PBMC-derived methylation signatures can discriminate clinical outcomes in EGFR-mutation LUAD subgroups.

Methods

We performed genome-wide methylation analysis of PBMCs from LUAD patients using the Infinium Methylation EPIC 850 K array. Clinical characteristics were associated with overall survival (OS) through Cox regression. Prognostic differentially methylated positions (DMPs) were identified via Lasso regression, followed by the construction of risk-score models. Functional enrichment (KEGG/GO) and tissue microarray-based immunohistochemistry (IHC) for FKBP4 expression (n = 90 LUAD samples) were conducted. Analyses were conducted in R 4.4.1 with curated Bioconductor packages.

Results

In the retrospective cohort of 174 Chinese LUAD patients (April 2014–September 2019), PBMC analysis of 128 cases revealed 12 hypomethylated DMPs were associated with OS. EGFR-mutant patients (n = 66) showed 325 significant DMPs (|Δβ|≥ 0.06, P ≤ 0.01), with four DMPs (cg05802998, cg19313959, cg00685115, cg15224444) independently predicting OS. The cg19313959 located in the TSS1500 region of FKBP4 gene (Δβ = 0.21) demonstrated the strongest methylation shift. Reduced FKBP4 protein expression was associated with improved survival (HR = 0.42, 95%CI 0.24–0.72). In EGFR-wildtype patients (n = 51), three prognostic DMPs emerged from 2,531 candidates. EGFR mutation-specific prognostic scoring models were established successfully, while pathway analyses revealed divergent biological processes between EGFR subgroups.

Conclusion

In this epigenome-wide study based on PBMCs in Chinese patients with LUAD, methylation signatures dependent on EGFR mutations and predictive of survival were identified.