Plasma glycosaminoglycans and cell-free DNA to discriminate benign and malignant lung diseases

We aimed to investigate the use of free glycosaminoglycan profiles (GAGomes) and cfDNA in plasma to differentiate between lung cancer and benign lung disease. GAGs were analyzed using the MIRAM(R) Free Glycosaminoglycan Kit with ultra-high-performance liquid chromatography and electrospray ionization triple-quadrupole mass spectrometry. We detected two GAGome features, 0S chondroitin sulfate (CS) and 4S CS, with cancer-specific changes. Based on the observed GAGome changes, we devised a model to predict lung cancer. The model, named the GAGome score, could detect lung cancer with 41.2% sensitivity (95% CI: 9.2-54.2%) at 96.4% specificity (CI: 95.2-100.0%, n=113). Furthermore, we found that the GAGome score, when combined with a cfDNA test, could increase the sensitivity for lung cancer from 42.6% (95% CI: 31.7-60.6%, cfDNA alone) to 70.5% (CI: 57.4 - 81.5%) at 95% specificity (CI: 75.1-100%, n=74). Notably, the combined GAGome and cfDNA testing improved the sensitivity, especially in early stages, relative to the cfDNA alone. Our findings show that plasma GAGome profiles can enhance cfDNA testing performance, highlighting the applicability of a multiomics approach in lung cancer diagnostics.