Early diagnosis of lung cancer is a critical priority in clinical practice. It may help reduce the rate of lung-cancer-related mortality, extend disease-free survival, and allow patients to live without ongoing medical interventions and complications. Although various diagnostic methods differentiate lung cancer malignancy from benign disease, their low accuracy makes them unfavorable.

DNA methylation, a key epigenetic alteration, has been implicated in the tumorigenesis of various cancers; however, its diagnostic value through circulating tumor DNA (ctDNA) remains unrealized in lung cancer. A recent study has shown that analysis of ctDNA methylation can aid the early diagnosis of non-small cell lung cancer (NSCLC).

This study, published in the Genes and Diseases journal by researchers at Sichuan University and Stanford University, used capture-based bisulfite sequencing to investigate the DNA methylation profiles of ctDNA in plasma and tissue samples obtained from patients with lung cancer or benign conditions. The analysis identified 276 differentially methylated markers specific to lung cancer.

Of the 276 predicted markers, six exhibited significantly different methylation statuses between lung cancer and benign conditions in the tissue cohort. Of these, two were found to be hypermethylated in lung cancer and four in benign diseases. Similarly, nine differentially methylated CpG sites (DMSs) were identified in the plasma cohort, of which only two were hypermethylated in lung cancer, while the remaining seven were hypomethylated. A diagnostic prediction model based on these patterns was able to successfully differentiate lung cancer from benign diseases in training and validation tissue cohorts. Although the diagnostic prediction model showed that plasma-derived methylation biomarkers can help early cancer diagnosis, their sensitivity and specificity were lower than the tissue-derived markers. Moreover, a significant correlation was noticed in the delta methylation levels between the tissue and plasma samples.

Methylation haplotype-based analysis identified 1222 differentially methylated regions in tissue samples enriched in DNA replication-related pathways. Additionally, significant correlations were observed between differential methylation patterns and clinical characteristics, especially between smokers and non-smokers in both tissue and plasma.

In conclusion, ctDNA methylation in both tissue and plasma can effectively differentiate malignancy from benign disease and holds great potential as a biomarker for early lung cancer diagnosis. In the future, integrating multi-modal information obtained from CT scanning, ctDNA mutations, and ctDNA methylation patterns could improve the sensitivity and specificity of early lung cancer diagnosis.

Reference

Title of the original paper: Diagnosis of early-stage non-small cell lung cancer using DNA methylation in tissue and plasma
DOI: https://doi.org/10.1016/j.gendis.2025.101548
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

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Funding information:
National Natural Science Foundation of China (No. 32201231)

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