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Simple Summary: Lung cancer is one of the deadliest cancers worldwide, and the prognosis is poor. The disease is potentially curable if detected at an early stage, but currently, the only widely implemented screening tool is low-dose computed tomography. Biomarkers such as methylated tumor DNA may be used for the early detection of lung cancer, and sputum is an appealing, non-invasive sample type. With this systematic review and meta-analysis, we aimed to identify all studies evaluating the quantitative methylation of tumor DNA in sputum samples for lung cancer detection. A systematic overview of all the available evidence may highlight areas of improvement as well as certain high-performing genes to prioritize in future studies. Lung cancer is the leading cause of cancer-related mortality worldwide. Early diagnosis is pivotal for the prognosis. There is a notable overlap between lung cancer and chronic bronchitis, and the potential use of methylated tumor DNA in sputum as a biomarker for lung cancer detection is appealing. This systematic review and meta-analysis followed the PRISMA 2020 statement. A comprehensive search was conducted in Embase, Medline, Web of Science, and the Cochrane Library, using these search strings: Lung cancer, sputum, and methylated tumor DNA. A total of 15 studies met the eligibility criteria. Studies predominantly utilized a case–control design, with sensitivity ranging from 10 to 93% and specificity from 8 to 100%. A meta-analysis of all genes across studies resulted in a summary sensitivity of 54.3% (95% CI 49.4–59.2%) and specificity of 79.7% (95% CI 75.0–83.7%). Notably, two less explored genes (TAC1, SOX17) demonstrated sensitivity levels surpassing 85%. The study's findings highlight substantial variations in the sensitivity and specificity of methylated tumor DNA in sputum for lung cancer detection. Challenges in reproducibility could stem from differences in tumor site, sample acquisition, extraction methods, and methylation measurement techniques. This meta-analysis provides a foundation for prioritizing high-performing genes, calling for a standardization and refinement of methodologies before potential application in clinical trials. [ABSTRACT FROM AUTHOR]

Simple Summary: Lung cancer is the leading cause of cancer-related deaths and has a poor prognosis. Early detection could improve survival for this large patient group. Certain genes are more frequently changed by methylation in cancer cells compared to healthy cells. This methylated tumor DNA is present in the blood in small quantities and has been suggested as a diagnostic biomarker in many diseases, including lung cancer. The aim of the present literature review was to identify and collate the current evidence on methylated circulating tumor DNA in blood samples as a diagnostic tool for lung cancer. A systematic collection and presentation of the existing evidence will aid future research in this field. Lung cancer is the leading cause of cancer-related deaths, and early detection is crucial for improving patient outcomes. Current screening methods using computed tomography have limitations, prompting interest in non-invasive diagnostic tools such as methylated circulating tumor DNA (ctDNA). The PRISMA guidelines for systematic reviews were followed. The electronic databases MEDLINE, Embase, Web of Science, and Cochrane Library were systematically searched for articles. The search string contained three main topics: Lung cancer, blood, and methylated ctDNA. The extraction of data and quality assessment were carried out independently by the reviewers. In total, 33 studies were eligible for inclusion in this systematic review and meta-analysis. The most frequently studied genes were SHOX2, RASSF1A, and APC. The sensitivity and specificity of methylated ctDNA varied across studies, with a summary sensitivity estimate of 46.9% and a summary specificity estimate of 92.9%. The area under the hierarchical summary receiver operating characteristics curve was 0.81. The included studies were generally of acceptable quality, although they lacked information in certain areas. The risk of publication bias was not significant. Based on the findings, methylated ctDNA in blood shows potential as a rule-in tool for lung cancer diagnosis but requires further research, possibly in combination with other biomarkers. [ABSTRACT FROM AUTHOR]