Multi-cancer risk prediction in asymptomatic adults using urinary glycosaminoglycan profiling

BACKGROUND: Cancer screening programs exclude individuals not considered at increased risk based on established risk factors such as age and tobacco use. No biomarker is currently routinely used to predict cancer risk. We investigated whether urinary glycosaminoglycan profiles (GAGomes) could predict multi-cancer risk in asymptomatic adults. METHODS: We conducted a case-cohort study of 5,436 healthy asymptomatic adults enrolled in the Lifelines Cohort Study (Netherlands), of whom 827 developed cancer within five years of urine sampling. Urinary GAGome were measured and aggregated into a GAGome score. Cox proportional hazards modeling was used to assess the association between the GAGome score and incident cancer, adjusting for established risk factors. Subjects were stratified into four risk groups (Low, Intermediate, High, and Very High GAGome risk) to estimate the observed 5-year risk. RESULTS: A standard deviation increase in the GAGome score was associated with a significantly elevated risk of incident cancer (HR = 1.66; 95% CI, 1.60-1.73) and accounted for 36% of the variance in cancer risk. The observed 5-year cancer risks across the four groups were 0.18% (Low), 2.3% (Intermediate), 7.6% (High), and 32% (Very High). Targeted screening of subjects classified as High GAGome risk would detect 54% of incident cancers, including 54% of in situ carcinomas, at a 17% false positive rate. CONCLUSIONS: Urinary GAGome identified a substantial subset of individuals at heightened cancer risk who would not be captured by current screening guidelines. IMPACT: These findings support the development of personalized cancer surveillance strategies incorporating GAGome-based risk stratification.