Competitive learning suggests circulating miRNA profiles for cancers decades prior to diagnosis.

MicroRNAs are regulators of gene expressionand may be key markers in liquid biopsy.Early diagnosis is an effective means to increase patients' overall survival. We generated genome-wide miRNA profiles from serum of patients and controls from the population-based Janus Serum Bank (JSB) and analysed them by bioinformatics and artificial intelligence approaches. JSB contains sera from 318,628 originally healthy persons, more than 96,000 of whom developed cancer. We selected 210 serum samples from patients with lung, colon or breast cancer at three time points prior to diagnosis (up to 32 years prior to diagnosis with median 5 years interval between TPs), one time-point after diagnosis and from individually matched controls. The controls were matched on age and year of all pre-diagnostic sampling time-points for the corresponding case. Using ANOVA we report 70 significantly deregulated markers (adjusted p-value<0.05). The driver for the significance was the diagnostic time point (miR-575, miR-6821-5p, miR-630 with adjusted p-values<10(-10)). Further, 91miRNAs were differently expressed in pre-diagnostic samples as compared to controls (nominal p < 0.05). Self-organized maps (SOMs)indicated larges effects in lung cancer samples while breast cancer samples showed the least pronounced changes. SOMsalsohighlighted cancer and time point specific miRNA dys-regulation. Intriguingly, a detailed breakdown of the results highlighted that 51% of all miRNAs were highly specific, either for a time-point or a cancer entity. Pathway analysis highlighted 12 pathways including Hipo signalling and ABC transporters.Our results indicate that tumours may be indicated by serum miRNAs decades prior the clinical manifestation.