Development and validation of a panel of five proteins as blood biomarkers for early detection of colorectal cancer
Received 16 June 2017
Accepted for publication 30 August 2017
Published 31 October 2017 Volume 2017:9 Pages 517—526
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Akshita Wason
Peer reviewer comments 4
Editor who approved publication: Professor Henrik Toft Sørensen
Hongda Chen,1,2 Jing Qian,1 Simone Werner,1 Katarina Cuk,1 Phillip Knebel,3 Hermann Brenner1,4,5
1Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; 2Program Office for Cancer Screening in Urban China, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 3Department of General, Visceral and Transplantation Surgery, University of Heidelberg, 4Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases, 5German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
Objective: 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.
Patients and methods: 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.
Results: 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.
Conclusion: The identified most promising biomarkers could contribute to the development of powerful blood-based tests for CRC screening in the future.
Keywords: amphiregulin, growth differentiation factor 15, adenoma, colorectal cancer, screening
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