Faecal Volatile Organic Compounds to Detect Colorectal Neoplasia in Lynch Syndrome—A Prospective Longitudinal Multicentre Study

ABSTRACT Background Non‐invasive biomarkers may reduce post‐colonoscopy colorectal cancer (CRC) rates and colonoscopy overuse in Lynch syndrome. Unlike faecal immunochemical test (FIT), faecal volatile organic compounds (VOCs) may accurately detect both advanced and non‐advanced colorectal neoplasia. Aim The aim of this study was to evaluate the potential of faecal VOCs—separately and with FIT—to guide optimal colonoscopy intervals in Lynch syndrome. Methods Prospective longitudinal multicentre study in which individuals with Lynch syndrome collected faeces before and after high‐quality surveillance colonoscopy. VOC‐patterns were analysed using field asymmetric ion mobility spectrometry (FAIMS) and gas chromatography‐ion mobility spectrometry (GC‐IMS) followed by machine learning pipelines, and combined with FIT at 2.55 μg Hb/g faeces. Gas chromatography time‐of‐flight mass spectrometry analysed individual VOC abundance. Results Among 200 included individuals (57% female, median 51 years), 62 had relevant neoplasia at colonoscopy: 3 CRC, 6 advanced adenoma (AA), 3 advanced serrated lesion (ASL), and 50 non‐advanced adenoma (NAA). Respective sensitivity and negative predictive value for CRC and AA (and also ASL in case of FAIMS) were 100% and 100% using FAIMS (54% specificity), and 89% and 99% using GC‐IMS (58% specificity). Respective sensitivity and specificity for any relevant neoplasia were 88% and 44% (FAIMS) and 84% and 28% (GC‐IMS); accuracy did not significantly improve upon VOC‐FIT. VOC‐patterns differed before and after polypectomy (AUC 0.70). NAA showed decreased faecal abundance of butanal, 2‐oxohexane, dimethyldisulphide and dimethyltrisulphide. Conclusions In Lynch syndrome, faecal VOCs may be a promising strategy for postponing colonoscopy and for follow‐up after polypectomy. Our results serve as a stepping stone for large validation studies. Trial Registration NL8749