Hongda Chen, Jing Qian, Simone Werner, Katarina Cuk, Phillip Knebel, Hermann Brenner

Reliable noninvasive biomarkers for early detection of colorectal cancer (CRC) are highly desirable for efficient population-based screening with high adherence rates. We aimed to discover and validate blood-based protein markers for the early detection of CRC. A two-stage design with a discovery and a validation set was used. In the discovery phase, plasma levels of 92 protein markers and serum levels of TP53 autoantibody were measured in 226 clinically recruited CRC patients and 118 controls who were free of colorectal neoplasms at screening colonoscopy. An algorithm predicting the presence of CRC was derived by Lasso regression and validated in a validation set consisting of all available 41 patients with CRC and a representative sample of 106 participants with advanced adenomas and 107 controls free of neoplasm from a large screening colonoscopy cohort (N=6018). Receiver operating characteristic (ROC) analyses were conducted to evaluate the diagnostic performance of individual biomarkers and biomarker combinations. An algorithm based on growth differentiation factor 15 (GDF-15), amphiregulin (AREG), Fas antigen ligand (FasL), Fms-related tyrosine kinase 3 ligand (Flt3L) and TP53 autoantibody was constructed. In the validation set, the areas under the curves of this five-marker algorithm were 0.82 (95% CI, 0.74-0.90) for detecting CRC and 0.60 (95% CI, 0.52-0.69) for detecting advanced adenomas. At cutoffs yielding 90% specificity, the sensitivities (95% CI) for detecting CRC and advanced adenomas were 56.4% (38.4%-71.8%) and 22.0% (13.4%-35.4%), respectively. The five-marker panel showed similar diagnostic efficacy for the detection of early- and late-stage CRC. The identified most promising biomarkers could contribute to the development of powerful blood-based tests for CRC screening in the future.