Abstract
Simple SummaryDiagnosing lung cancer requires invasive procedures with high risk of complications. Methylated tumor-specific DNA has been suggested as a biomarker for lung cancer. The present study aimed to develop and validate the biomarker methylated HOXA9 in fluid from the lung collected during bronchoscopy. This biomarker has a clinically relevant sensitivity and specificity for the diagnosis of lung cancer. Future research should focus on determining the optimal combination of biomarker and biologic specimen.Diagnosing lung cancer requires invasive procedures with high risk of complications. Methylated tumor DNA in bronchial lavage has previously shown potential as a diagnostic biomarker. We aimed to develop and validate methylated HOXA9 in bronchial lavage as a diagnostic biomarker of lung cancer. Participants were referred on suspicion of lung cancer. Ten mL lavage fluid was collected at bronchoscopy for analysis of methylated HOXA9 based on droplet digital PCR according to our previously published method. HOXA9 status was compared with the final diagnosis. The Discovery and Validation cohorts consisted of 101 and 95 consecutively enrolled participants, respectively. In the discovery cohort, the sensitivity and specificity were 73.1% (95% CI 60.9–83.2%) and 85.3% (95% CI 68.9–95.0%), respectively. In the validation cohort, the values were 80.0% (95% CI 66.3–90.0%) and 75.6% (95% CI 60.5–87.1%), respectively. A multiple logistic regression model including age, smoking status, and methylated HOXA9 status resulted in an AUC of 84.9% (95% CI 77.3–92.4%) and 85.9% (95% CI 78.4–93.4%) for the Discovery and Validation cohorts, respectively. Methylated HOXA9 in bronchial lavage holds potential as a supplementary tool in the diagnosis of lung cancer with a clinically relevant sensitivity and specificity. It remained significant when adjusting for age and smoking status.
Highlights
Lung cancer is considered the deadliest cancer worldwide [1] and is often diagnosed at a late stage [2,3,4]
Screening with low-dose computed tomography (CT) scans is recommended in the USA and some European countries based on the results from large screening trials, including the US-based National Lung Screening Trial (NLST) [5] and the DutchBelgian Nederlands-Leuvens Longkanker Screenings Onderzoek (NELSON) [6]
We conclude that methylated homeobox A9 (HOXA9) in bronchial lavage holds potential as a supplementary tool in the diagnosis of lung cancer because it has a clinically relevant sensitivity and specificity
Summary
Lung cancer is considered the deadliest cancer worldwide [1] and is often diagnosed at a late stage [2,3,4]. Screening with low-dose computed tomography (CT) scans is recommended in the USA and some European countries based on the results from large screening trials, including the US-based National Lung Screening Trial (NLST) [5] and the DutchBelgian Nederlands-Leuvens Longkanker Screenings Onderzoek (NELSON) [6] These studies concluded that there was a reduction in mortality of at least 20% in the CT-screened cohort. Studies have indicated that small or early-stage lung tumors do not shed as much DNA into the circulation as larger tumors and are more difficult to detect in the blood [13,14] This could be overcome by using material collected closer to the tumor site, as this material likely contains more tumor DNA. We conclude that methylated HOXA9 in bronchial lavage holds potential as a supplementary tool in the diagnosis of lung cancer because it has a clinically relevant sensitivity and specificity
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