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Open AccessArticle

Evaluation and Validation of Plasma Proteins Using Two Different Protein Detection Methods for Early Detection of Colorectal Cancer

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Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), 69120 Heidelberg, Germany
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Medical Faculty Heidelberg, University of Heidelberg, 69120 Heidelberg, Germany
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Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
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German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
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Division of Biostatistics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
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University of Victoria-Genome British Columbia Proteomics Centre, University of Victoria (UVic), Victoria, BC V8Z 7X8, Canada
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Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC V8P 5C2, Canada
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Segal Cancer Proteomics Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada
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Gerald Bronfman Department of Oncology, Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada
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Author to whom correspondence should be addressed.
Cancers 2019, 11(10), 1426; https://doi.org/10.3390/cancers11101426
Received: 29 July 2019 / Revised: 11 September 2019 / Accepted: 17 September 2019 / Published: 25 September 2019
Objective: Plasma protein biomarkers could be an efficient alternative for population-based screening for early detection of colorectal cancer (CRC). The objective of this study was to evaluate and validate plasma proteins individually and as a signature for early detection of CRC. Methods: In a three-stage design, proteins were measured firstly by liquid chromatography/multiple reaction monitoring-mass spectrometry (LC/MRM-MS) and later by proximity extension assay (PEA) in a discovery set consisting of 96 newly diagnosed CRC cases and 94 controls free of neoplasms at screening colonoscopy. Two algorithms (one for each measurement method) were derived by Lasso regression and .632+ bootstrap based on 11 proteins that were included in both the LC/MRM-MS and PEA measurements. Additionally, another algorithm was constructed from the same eleven biomarkers plus amphireglin, the most promising protein marker in the PEA measurements that had not been available from the LC/MRM-MS measurements. Lastly the three prediction signatures were validated with PEA in independent samples of participants of screening colonoscopy (CRC (n = 56), advanced adenoma (n = 101), and participants free of neoplasm (n = 102)). Results: The same four proteins were included in all three prediction signatures; mannan binding lectin serine protease 1, osteopontin, serum paraoxonase lactonase 3 and transferrin receptor protein 1, and the third prediction signature additionally included amphiregulin. In the independent validation set from a true screening setting, the five-marker blood-based signature including AREG presented areas under the curves of 0.82 (95% CI, 0.74–0.89), 0.86 (95% CI, 0.77–0.92) and 0.76 (95% CI, 0.64–0.86) for all, early and late stages CRC, respectively. Conclusion: Two different measurement methods consistently identified four protein markers and an algorithm additionally including amphiregulin, a marker measured by PEA only, showed promising performance for detecting early stage CRC in an independent validation in a true screening setting. These proteins may be potential candidates for blood-based tests for early detection of CRC. View Full-Text
Keywords: colorectal cancer; early detection; screening; biomarkers; prevention; proximity extension assay; LC/MRM-MS; proteomics colorectal cancer; early detection; screening; biomarkers; prevention; proximity extension assay; LC/MRM-MS; proteomics
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Bhardwaj, M.; Gies, A.; Weigl, K.; Tikk, K.; Benner, A.; Schrotz-King, P.; Borchers, C.H.; Brenner, H. Evaluation and Validation of Plasma Proteins Using Two Different Protein Detection Methods for Early Detection of Colorectal Cancer. Cancers 2019, 11, 1426.

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