Differentially expressed microRNAs in prediagnostic serum linked to lung cancer up to eight years before diagnosis in prospective, population-based cohorts: A HUNT study.

person Olav Toai Duc Nguyen Norwegian University of Science and Technology (NTNU), Department of Clinical Research and Molecular Medicine, Trondheim, Norway info_outline Olav Toai Duc Nguyen, Yannis Fotopoulos, Therese Haugdahl Nøst, Maria Markaki, Vincenzo Lagani, Pål Sætrom, Ioannis Tsamardinos, Oluf Dimitri D. Røe

Authors person Olav Toai Duc Nguyen Norwegian University of Science and Technology (NTNU), Department of Clinical Research and Molecular Medicine, Trondheim, Norway info_outline Olav Toai Duc Nguyen, Yannis Fotopoulos, Therese Haugdahl Nøst, Maria Markaki, Vincenzo Lagani, Pål Sætrom, Ioannis Tsamardinos, Oluf Dimitri D. Røe Organizations Norwegian University of Science and Technology (NTNU), Department of Clinical Research and Molecular Medicine, Trondheim, Norway, University of Crete, Department of Computer Science, Heraklion, Greece, UiT The Arctic University of Norway, Department of Community Medicine, Faculty of Health Sciences, Tromsø, Norway, Institute of Applied and Computational Mathematics, FORTH, Heraklion, Greece, Institute of Chemical Biology, Ilia State University, Tibilisi, Georgia, Norwegian University of Science and Technology (NTNU), Department of Clinical and Molecular Medicine, Trondheim, Norway Abstract Disclosures Research Funding Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology Background: With lung cancer incidence and mortality on the rise, blood biomarkers are increasingly in demand for early detection. The aim of this study is to discover and validate novel biomarkers based on next-generation sequencing performed on blood samples from non-cancer, ever-smokers up to eight years prior to diagnosis. Methods: Initial consideration was given to serum samples from the population-based prospective HUNT2 and HUNT3 cohorts, age > 18 (n = 98,737). Inclusion criteria for cases were ever-smokers, no prior cancer at study entry, and 0–8 years between blood sampling and lung cancer diagnosis in the discovery and 0-4 years in the validation cohort. Among future cases, equal numbers of adenocarcinoma, squamous cell carcinoma and small-cell lung carcinoma were included. Every subsequent case of lung cancer had a matched control, ratio 1:1. The controls were matched for sex, age at study entry, pack-years, smoking cessation duration, comparable HUNT Lung Cancer Model risk score and no cancer diagnosis until the end of the study. The total number of serum samples included in the discovery and validation dataset were 240 (from HUNT2) and 72 (from HUNT3), respectively. The samples were analyzed by genome-wide small RNA seq (Illumina). Results: When we contrasted all cases against all controls, nine differentially expressed microRNAs with AUC > 0.60 (FDR < 0.25) and total raw count of > 0.5 appeared in common in the discovery and validation datasets. Among these, three microRNAs were associated with non-small cell metastatic with mean AUC of 0.65 and 0.76 in the discovery and validation datasets, respectively. Furthermore, the signature of these three microRNAs in combination reached an AUC of 0.75 (discovery) and 0.90 (validation). Conclusions: Up to eight years before diagnosis, a small number of substantially differentially expressed microRNAs were found in serum. These intriguing microRNAs can potentially function as early diagnostic indicators for lung cancer, either alone or in combination. Further investigation and validation of these results in a larger prospective serum dataset are required.