Methylated Circulating Tumor DNA in Blood as a Tool for Diagnosing Lung Cancer: A Systematic Review and Meta-Analysis

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. ABSTRACT: 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.