Abstract
BACKGROUND: Individual plasma proteins have been identified as minimally invasive biomarkers for lung cancer diagnosis with potential utility in early detection. Plasma proteomes provide insight into contributing biological factors; we investigated their potential for future lung cancer prediction. METHODS: The Olink® Explore-3072 platform quantitated 2941 proteins in 496 Liverpool Lung Project plasma samples, including 131 cases taken 1-10 years prior to diagnosis, 237 controls, and 90 subjects at multiple times. 1112 proteins significantly associated with haemolysis were excluded. Feature selection with bootstrapping identified differentially expressed proteins, subsequently modelled for lung cancer prediction and validated in UK Biobank data. FINDINGS: For samples 1-3 years pre-diagnosis, 240 proteins were significantly different in cases; for 1-5 year samples, 117 of these and 150 further proteins were identified, mapping to significantly different pathways. Four machine learning algorithms gave median AUCs of 0.76-0.90 and 0.73-0.83 for the 1-3 year and 1-5 year proteins respectively. External validation gave AUCs of 0.75 (1-3 year) and 0.69 (1-5 year), with AUC 0.7 up to 12 years prior to diagnosis. The models were independent of age, smoking duration, cancer histology and the presence of COPD. INTERPRETATION: The plasma proteome provides biomarkers which may be used to identify those at greatest risk of lung cancer. The proteins and the pathways are different when lung cancer is more imminent, indicating that both biomarkers of inherent risk and biomarkers associated with presence of early lung cancer may be identified. FUNDING: Janssen Pharmaceuticals Research Collaboration Award; Roy Castle Lung Cancer Foundation.