The diagnostic potential of urinary volatile organic compounds for colorectal neoplasia in Lynch syndrome—A prospective longitudinal study

Post-colonoscopy colorectal cancer (CRC) rates and colonoscopy burden are considerable in Lynch syndrome. Urinary volatile organic compounds (VOCs) have shown promise as a patient-friendly alternative to faecal biomarkers for colorectal neoplasia detection. To evaluate the potential of urinary VOCs to guide optimal colonoscopy intervals in Lynch syndrome, we performed an exploratory prospective longitudinal study in urine collected by individuals with Lynch syndrome before and after colonoscopy. VOC patterns were analysed by field asymmetric ion mobility spectrometry (FAIMS) and gas chromatography-ion mobility spectrometry (GC-IMS) followed by machine learning algorithms. Gas chromatography time-of-flight mass spectrometry analysed the abundance of individual VOCs. Among 98 included individuals (median 51y, 58% female), 34 had relevant neoplasia at colonoscopy, including 28 non-advanced adenomas, 3 advanced adenomas, 2 CRCs, and 1 advanced serrated lesion. For GC-IMS, the respective sensitivity and negative predictive value for relevant neoplasia were 65% and 79% (70% specificity); for FAIMS, 74% and 75% (42% specificity). VOC patterns differed before and after polypectomy (AUC 0.84), while after polypectomy they resembled those of individuals without neoplasia (AUC 0.52). Non-advanced adenoma presence was associated with increased urinary abundance of decanoic acid (fatty acid). Diagnostic accuracy of urinary VOC patterns for relevant neoplasia was influenced by sample size and external confounders and was lower than for faecal VOC patterns among 50 individuals who had also collected faeces. Urinary VOCs hold promise as non-invasive biomarkers for postponing colonoscopy and for follow-up after polypectomy in Lynch syndrome, though large validation studies are needed that also assess stability and accuracy compared to faecal VOCs.