Diagnostic performance of plasma DNA methylation profiles in lung cancer, pulmonary fibrosis and COPD

Andreas Weinhäusel 1,*, Matthias Wielscher1, Klemens Vierlinger1, Rolf Ziesche2,
Andrea Gsur2, Christa Noehammer1
1 AIT Austrian Institute of Technology GmbH, Molekulare Diagnostik, Austria
2 Medical University Vienna, Austria 

Disease-specific alterations of the cell-free DNA methylation status are frequently found in serum samples and are currently considered to be suitable biomarkers. Candidate markers were identified by bisulfite conversion-based genome-wide methylation screening of lung tissue from lung cancer, fibrotic ILD, and COPD. cfDNA from 400 l serum (n=204) served to test the diagnos- tic performance of these markers. Following methylation-sensitive restriction enzyme digestion and enrichment of methylated DNA via targeted amplification (multiplexed MSRE enrichment), a total of 96 markers were addressed by highly parallel qPCR.
Lung cancer was efficiently separated from non-cancer and con- trols with a sensitivity of 87.8%, (95%CI: 0.67–0.97) and specificity 90.2%, (95%CI: 0.65–0.98). Cancer was distinguished from ILD with a specificity of 88%, (95%CI: 0.57–1), and COPD from cancer with a specificity of 88% (95%CI: 0.64–0.97). Separation of ILD from COPD and controls was possible with a sensitivity of 63.1% (95%CI: 0.4–0.78) and a specificity of 70% (95%CI: 0.54–0.81). The results were confirmed using an independent sample set (n = 46) by use of the four top markers discovered in the study (HOXD10, PAX9, PTPRN2, and STAG3) yielding an AUC of 0.85 (95%CI: 0.72–0.95). This technique was capable of distinguishing interrelated complex pulmonary diseases suggesting that multiplexed MSRE enrichment might be useful for simple and reliable diagnosis of diverse multi- factorial disease states.

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