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<p>Lung cancer continues to constitute the foremost cause of cancer-related mortality globally. Early detection of biomarkers and their correlation with therapeutic survival may improve the outcomes. We have explored the methylation level of a panel of genes (<i>CDKN2A, RASSF1A,</i> and <i>MGMT</i>) in genomic DNA (gDNA) of tumour tissue compared to tumour-free tissue and cell-free DNA (cfDNA) of Non-Small Cell Lung Cancer (NSCLC) case versus control using methylation-specific PCR (MSP) and quantitative methylation-specific PCR (QMSP), and established cfDNA as a tissue-mirror biomarker. Furthermore, a model was constructed using overall survival (OS) and progression-free survival (PFS) following chemotherapy, based on the methylation status of three genes in cfDNA. Significantly higher methylation levels were observed in tumor tissue for all three genes, with similar patterns detected in cfDNA. The calculated Cohen's kappa showed a fair and moderate level of correlation between cfDNA and tissue. The sensitivity and specificity were 37.36–64.84% and 86.81–89.81%, respectively. The methylation was significantly higher in the early stage of LC (stage II), and increased with metastasis. The gene methylation was observed to be higher in patients with shorter survival period (<i>MGMT</i>: HR = 2.45, CI: 1.4–4.1, <i>p</i> ≤ 0.001, <i>CDKN2A</i>: HR = 2.31, CI: 1.3–4.0, <i>p</i> ≤ 0.01, <i>RASSF1A</i>: 2.51, CI: 1.4–4.7, <i>p</i> ≤ 0.001). PFS analysis revealed that patients receiving chemotherapy exhibited higher unmethylated genes in cfDNA (QMSP cut-off ≥ 4) with significantly longer survival than those with methylated genes. Results indicated that promoter methylation of selected genes in cfDNA may serve as a promising biomarker and may be used as a predictor for pemetrexed plus cisplatin and gemcitabine plus cisplatin chemotherapy.</p>

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Methylation based predictive biomarkers panel of genes for early detection and chemotherapy response in NSCLC

  • 期刊论文

  • 发表日期：

    2025年12月3日

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  • Supriya Karpathak,
  • Rajiv Garg,
  • Mohammad Kaleem Ahmad,
  • Anand Srivastava,
  • Anurag Kumar Srivastav,
  • Neeraj Tiwari,

摘要

Lung cancer continues to constitute the foremost cause of cancer-related mortality globally. Early detection of biomarkers and their correlation with therapeutic survival may improve the outcomes. We have explored the methylation level of a panel of genes (CDKN2A, RASSF1A, and MGMT) in genomic DNA (gDNA) of tumour tissue compared to tumour-free tissue and cell-free DNA (cfDNA) of Non-Small Cell Lung Cancer (NSCLC) case versus control using methylation-specific PCR (MSP) and quantitative methylation-specific PCR (QMSP), and established cfDNA as a tissue-mirror biomarker. Furthermore, a model was constructed using overall survival (OS) and progression-free survival (PFS) following chemotherapy, based on the methylation status of three genes in cfDNA. Significantly higher methylation levels were observed in tumor tissue for all three genes, with similar patterns detected in cfDNA. The calculated Cohen's kappa showed a fair and moderate level of correlation between cfDNA and tissue. The sensitivity and specificity were 37.36–64.84% and 86.81–89.81%, respectively. The methylation was significantly higher in the early stage of LC (stage II), and increased with metastasis. The gene methylation was observed to be higher in patients with shorter survival period (MGMT: HR = 2.45, CI: 1.4–4.1, p ≤ 0.001, CDKN2A: HR = 2.31, CI: 1.3–4.0, p ≤ 0.01, RASSF1A: 2.51, CI: 1.4–4.7, p ≤ 0.001). PFS analysis revealed that patients receiving chemotherapy exhibited higher unmethylated genes in cfDNA (QMSP cut-off ≥ 4) with significantly longer survival than those with methylated genes. Results indicated that promoter methylation of selected genes in cfDNA may serve as a promising biomarker and may be used as a predictor for pemetrexed plus cisplatin and gemcitabine plus cisplatin chemotherapy.