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Circulating methylated promoters of HK2 and EGFR as biomarkers in the early detection of cancer
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DOI：10.3389/fonc.2026.1847436.png)
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Abstract
En 中文
IntroductionAberrant methylation of promoter DNA regions is a well-known epigenetic hallmark of cancer. Previous studies on tumorigenic mouse models revealed that abnormal methylation in the promoter regions of selected genes occurs during the early stages of tumorigenesis. To explore further changes in the blood circulation of humans; we analysed the methylation levels of tumour- derived DNA in the plasma of selected samples; to develop a preliminary non-invasive method for early cancer detection.Materials and methodsFollowing earlier epigenetic modifications in tumorigenic mouse models; four genes (HK2; EGFR; DDIT3; and VEGFA) with differentially methylated promoters were selected for the present study. Targeted gene-specific methylated and unmethylated primers were designed by using the Methprimer program; and blood was drawn from clinically diagnosed cancer patients and healthy controls. cfDNA was isolated; bisulfite-treated; and analysed by qMSP. ROC curve analysis was conducted for genes that were found to be amplified; and validation was conducted by using in silico data from the MethMarkerDB across 10 cancer types.ResultsOut of the four genes; HK2 and EGFR alone exhibited successful amplification and significantly higher methylation in the circulation of cancer samples. ROC analysis showed good diagnostic performance of HK2; AUC = 0.8288; and EGFR AUC = 0.9405. Relative methylation analysis in 12 different cancer types showed elevated methylation levels for HK2 and EGFR in liver; lung; prostate; ovarian; colon; stomach; breast; endometrial; and cervical cancers. In silico validation in the MethMarkerDB showed the existence of hypermethylation in tumour WGBS compared to healthy controls across 10 cancer types.DiscussionAbnormal promoter methylation is an early event in tumorigenesis and can be detected in circulating cfDNA. The present study analysed the diagnostic potential of HK2 and EGFR promoter methylation in cfDNA as non-invasive early cancer biomarkers. The results showed significant hypermethylation in cancer patients with strong diagnostic performance (AUC = 0.8288 and 0.9405).
Keywords:
EGFR
promoter methylation
DNA methylation
HK2
circulating free DNA
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