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Meta-Analysis
. 2025 Jun 2;14(1):120.
doi: 10.1186/s13643-025-02860-w.

Circulating cell-free DNA methylation as biomarker for lung cancer detection: a systematic review and meta-analysis of diagnostic studies

Diana Inês Machado #  1   2 , Tiago Brito-Rocha #  1 , Sofia Salta  1 , Teresa Monjardino  3 , Rui Henrique  4   5   6 , Carmen Jerónimo  7   8
Affiliations
Meta-Analysis

Circulating cell-free DNA methylation as biomarker for lung cancer detection: a systematic review and meta-analysis of diagnostic studies

Diana Inês Machado et al. Syst Rev. .

Abstract

Lung cancer (LC) is the most incident malignancy and a leading cause of cancer-related fatalities. The lack of dissemination of effective screening tools hinders early detection, resulting in late-stage diagnosis, mostly associated with high mortality. Gene-specific methylation alterations detected in plasma or serum circulation cell-free DNA (ccfDNA) have been investigated as a possible screening tool. Thus, the main aim of this systematic review and meta-analysis was to critically assess published data on the use of ccfDNA methylation-based biomarkers for detection of LC. PubMed, including MEDLINE and Scopus databases, were systematically searched for eligible articles evaluating the diagnostic performance of ccfDNA methylation alterations in that setting. A bivariate random-effect model was employed to calculate pool estimated sensitivity and specificity. Accuracy subgroup analyses, according to histological subtype, stage, and smoker status were carried out. A total of 1961 articles were retrieved, of which 44 met inclusion criteria. The meta-analysis generated a pooled sensitivity of 54% (CI 95% 48-60%) and a pooled specificity of 86% (CI 95% 83-87%) for LC detection. The most frequently tested host-genome methylation markers were RASSF1 A, APC, SHOX2, SOX17, and HOXA9. Overall, methylation analysis of ccfDNA detects LC with high specificity but modest sensitivity. Further research is required to improve diagnostic performance, establish methodological standards and determine whether this might complement existing screening strategies to increase effectiveness. Systematic review registration PROSPERO CRD42023408964.

Keywords: Biomarkers; DNA methylation; Early detection; Liquid biopsies; Lung cancer; Screening.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
PRISMA flowchart of this systematic review and studies included in the meta-analysis
Fig. 2
Fig. 2
Quality assessment of studies using the QUADAS-2 tool. The top panel depicts the risk of bias and the bottom panel the concerns regarding applicability
Fig. 3
Fig. 3
SROC graphs of ccfDNA methylation markers for lung cancer detection. A All single and panel markers. B Single markers only
Fig. 4
Fig. 4
SROC graphs curves off ccfDNA methylation markers for lung cancer detection. A Refer to NSCLC. B Refer to SCLC. C Refer to ADC. D Refer to SCC
Fig. 5
Fig. 5
SROC graphs curves of ccfDNA methylation markers to lung cancer detection. A Refer to early stage cancer. B Refer to late stage cancer
Fig. 6
Fig. 6
SROC graphs curves of ccfDNA methylation markers to lung cancer detection. A Refer to smokers. B Refer to non-smokers
Fig. 7
Fig. 7
SROC curves of ccfDNA methylation markers to lung cancer detection. A Refer to SHOX2. B Refer to SOX17. C Refer to HOXA9. D Refer to RASSF1 A. E Refer to APC
Fig. 8
Fig. 8
Positive predictive values (PPV, red) and negative predictive values (NPV, blue) of ccfDNA methylation markers considering all studies with all methylation markers
See this image and copyright information in PMC

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