title: Prospective evaluation of 64 serum autoantibodies as biomarkers for early detection of colorectal cancer in a true screening setting.
abstract: Novel blood-based screening tests are strongly desirable for early detection of colorectal cancer (CRC). We aimed to identify and evaluate autoantibodies against tumor-associated antigens as biomarkers for early detection of CRC. 380 clinically identified CRC patients and samples of participants with selected findings from a cohort of screening colonoscopy participants in 2005-2013 (N=6826) were included in this analysis. Sixty-four serum autoantibody markers were measured by multiplex bead-based serological assays. A two-step approach with selection of biomarkers in a training set, and validation of findings in a validation set, the latter exclusively including participants from the screening setting, was applied. Anti-MAGEA4 exhibited the highest sensitivity for detecting early stage CRC and advanced adenoma. Multi-marker combinations substantially increased sensitivity at the price of a moderate loss of specificity. Anti-TP53, anti-IMPDH2, anti-MDM2 and anti-MAGEA4 were consistently included in the best-performing 4-, 5-, and 6-marker combinations. This four-marker panel yielded a sensitivity of 26% (95% CI, 13-45%) for early stage CRC at a specificity of 90% (95% CI, 83-94%) in the validation set. Notably, it also detected 20% (95% CI, 13-29%) of advanced adenomas. Taken together, the identified biomarkers could contribute to the development of a useful multi-marker blood-based test for CRC early detection.
authors.affiliation: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Hongda
authors.initials: H
authors.lastname: Chen
authors.affiliation: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Werner
authors.affiliation: Division of Molecular Diagnostics of Oncogenic Infections, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Butt
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases (NCT), Internal Medicine VI, University of Heidelberg, Heidelberg, Germany.
authors.forename: Inka
authors.initials: I
authors.lastname: Zörnig
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Phillip
authors.initials: P
authors.lastname: Knebel
authors.affiliation: Division of Molecular Diagnostics of Oncogenic Infections, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Angelika
authors.initials: A
authors.lastname: Michel
authors.affiliation: GMP & T cell Therapy Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Stefan B
authors.initials: SB
authors.lastname: Eichmüller
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases (NCT), Internal Medicine VI, University of Heidelberg, Heidelberg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Jäger
authors.affiliation: Division of Molecular Diagnostics of Oncogenic Infections, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Waterboer
authors.affiliation: Division of Molecular Diagnostics of Oncogenic Infections, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Pawlita
authors.affiliation: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.|German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Brenner
mesh_terms: D000236:Adenoma / Q000097:blood / Q000175:diagnosis / Q000276:immunology; D000368:Aged; D000951:Antigens, Neoplasm / Q000276:immunology; D001323:Autoantibodies / Q000097:blood*; D014408:Biomarkers, Tumor / Q000097:blood* / Q000276:immunology; D015179:Colorectal Neoplasms / Q000097:blood* / Q000175:diagnosis / Q000276:immunology; D055088:Early Detection of Cancer / Q000379:methods*; D005260:Female; D006801:Humans; D008297:Male; D008403:Mass Screening / Q000379:methods*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000276:immunology; D011446:Prospective Studies; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
chemical_list: D000951:Antigens, Neoplasm; D001323:Autoantibodies; D014408:Biomarkers, Tumor; C095204:MAGEA4 protein, human; D009363:Neoplasm Proteins
keywords: autoantibody; colorectal cancer; diagnosis; screening setting; tumor-associated antigens