{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T21:10:21Z","timestamp":1777324221272,"version":"3.51.4"},"reference-count":43,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2024,10,29]],"date-time":"2024-10-29T00:00:00Z","timestamp":1730160000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NextGenerationEU","award":["CUP B63C22000680007"],"award-info":[{"award-number":["CUP B63C22000680007"]}]},{"name":"NextGenerationEU","award":["CUP B53D23007910006"],"award-info":[{"award-number":["CUP B53D23007910006"]}]},{"name":"EU funding within the NextGenerationEU, with the Italian Ministry of University and Research (MUR)","award":["CUP B63C22000680007"],"award-info":[{"award-number":["CUP B63C22000680007"]}]},{"name":"EU funding within the NextGenerationEU, with the Italian Ministry of University and Research (MUR)","award":["CUP B53D23007910006"],"award-info":[{"award-number":["CUP B53D23007910006"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Non-Small Cell Lung Cancer (NSCLC) remains a challenging disease to manage with effectiveness. Early detection and precise monitoring are crucial for improving patient outcomes. Circulating tumor DNA (ctDNA) offers a non-invasive cancer detection and monitoring method. Emerging biomarkers, such as ctDNA methylation, have shown promise in enhancing diagnostic accuracy and prognostic assessment in NSCLC. In this review, we examined the current evidence regarding ctDNA methylation\u2019s role in NSCLC detection through a systematic review of the existing literature and meta-analysis. Methods: We systematically searched PubMed, Medline, Embase, and Web of Science databases up to 26 June 2024 for studies on the role of ctDNA methylation analysis in NSCLC patients. We included studies from 2010 to 2024 on NSCLC patients. We excluded case reports, non-English articles, studies on cell lines or artificial samples, those without cfDNA detection, prognostic studies, and studies with non-extractable data or mixed cancer types. Funnel plots were visually examined for potential publication bias, with a p value &lt; 0.05 indicating bias. Meta-analysis was conducted using R packages (meta, forestplot, and mada). Combined sensitivity, specificity, positive likelihood ratio (LR+), negative likelihood ratio (LR\u2212), positive and negative predictive values, diagnostic odds ratio (DOR), and 95% confidence intervals (95% CI) were calculated. A summary receiver operating characteristic curve (SROC) and area under the curve (AUC) with related Standard Error (SE) were used to evaluate the overall diagnostic performance. Additionally, RASSF1A, APC, SOX17, SEPT9, and RAR\u03b22 were analyzed, since their methylation was assessed in two or more studies. Results: From 38 candidate papers, we finally identified 12 studies, including 472 NSCLC patients. The pooled sensitivity was 0.62 (0.47\u20130.77) and the specificity was 0.90 (0.85\u20130.94). The diagnostic odds ratio was 15.6 (95% CI 9.36\u201326.09) and the area under the curve was 0.249 (SE = 0.138). The positive and negative predictive values were 5.38 (95% CI 3.89\u20137.44) and 0.34 (95% CI 0.22\u20130.54), respectively. For single genes, the specificity reached 0.83~0.96, except for RAR\u03b22, but the sensitivity was relatively low for each gene. Significant heterogeneity across the included studies, the potential publication bias for specificity (p = 0.0231), and the need to validate the clinical utility of ctDNA methylation for monitoring treatment response and predicting outcomes in NSCLC patients represent the main limitations of this study. Conclusions: These results provide evidence of the significant potential of ctDNA methylation as a valuable biomarker for improving the diagnosis of NSCLC, advocating for its integration into clinical practice to enhance patient management.<\/jats:p>","DOI":"10.3390\/cancers16213641","type":"journal-article","created":{"date-parts":[[2024,10,29]],"date-time":"2024-10-29T04:51:33Z","timestamp":1730177493000},"page":"3641","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["The Evidence Base for Circulating Tumor DNA-Methylation in Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-0549-4953","authenticated-orcid":false,"given":"Debora","family":"Maffeo","sequence":"first","affiliation":[{"name":"Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy"},{"name":"Cancer Genomics and Systems Biology Lab, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6469-2564","authenticated-orcid":false,"given":"Angela","family":"Rina","sequence":"additional","affiliation":[{"name":"Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy"},{"name":"UOC Laboratorio di Assistenza e Ricerca Traslazionale, Dipartimento di Terapie cellulari, Ematologia e Medicina di Laboratorio, Azienda Ospedaliero-Universitaria Senese, 53100 Siena, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4566-6124","authenticated-orcid":false,"given":"Viola Bianca","family":"Serio","sequence":"additional","affiliation":[{"name":"Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy"},{"name":"Cancer Genomics and Systems Biology Lab, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7760-9701","authenticated-orcid":false,"given":"Athina","family":"Markou","sequence":"additional","affiliation":[{"name":"Lab of Analytical Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, 15772 Athens, Greece"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9174-8548","authenticated-orcid":false,"given":"Tomasz","family":"Powr\u00f3zek","sequence":"additional","affiliation":[{"name":"Department of Human Physiology, University of Lublin, 20080 Lublin, Poland"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3151-0367","authenticated-orcid":false,"given":"Vera","family":"Const\u00e2ncio","sequence":"additional","affiliation":[{"name":"Cancer Biology and Epigenetics Group, Research Center (CI-IPOP)\/CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC), 4200-072 Porto, Portugal"}]},{"given":"Sandra P.","family":"Nunes","sequence":"additional","affiliation":[{"name":"Cancer Biology and Epigenetics Group, Research Center (CI-IPOP)\/CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC), 4200-072 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4186-5345","authenticated-orcid":false,"given":"Carmen","family":"Jer\u00f3nimo","sequence":"additional","affiliation":[{"name":"Cancer Biology and Epigenetics Group, Research Center (CI-IPOP)\/CI-IPOP@RISE (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC), 4200-072 Porto, Portugal"},{"name":"Department of Pathology and Molecular Immunology, ICBAS-School of Medicine & Biomedical Sciences, University of Porto, 4099-002 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4074-4242","authenticated-orcid":false,"given":"Alfonso","family":"Calvo","sequence":"additional","affiliation":[{"name":"Program in Solid Tumors, CIMA, Cancer Center Cl\u00ednica Universidad de Navarra (CCUN), Instituto de Investigaci\u00f3n Sanitaria de Navarra (IDISNA), Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, 31008 Pamplona, Spain"},{"name":"CIBERONC, ISCIII, 28029 Madrid, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1992-1654","authenticated-orcid":false,"given":"Francesca","family":"Mari","sequence":"additional","affiliation":[{"name":"UOC Laboratorio di Assistenza e Ricerca Traslazionale, Dipartimento di Terapie cellulari, Ematologia e Medicina di Laboratorio, Azienda Ospedaliero-Universitaria Senese, 53100 Siena, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5634-031X","authenticated-orcid":false,"given":"Elisa","family":"Frullanti","sequence":"additional","affiliation":[{"name":"Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy"},{"name":"Cancer Genomics and Systems Biology Lab, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy"}]},{"given":"Diletta","family":"Rosati","sequence":"additional","affiliation":[{"name":"Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy"},{"name":"Cancer Genomics and Systems Biology Lab, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3014-1552","authenticated-orcid":false,"given":"Maria","family":"Palmieri","sequence":"additional","affiliation":[{"name":"Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy"},{"name":"Cancer Genomics and Systems Biology Lab, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-3-319-24223-1_1","article-title":"Lung Cancer Statistics","volume":"893","author":"Torre","year":"2016","journal-title":"Adv. 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