Cancer biomarkers defined by autoantibody signatures to aberrant O-glycopeptide epitopes.
Autoantibodies to cancer antigens hold promise as biomarkers for early detection of cancer. Proteins that are aberrantly processed in cancer cells are likely to present autoantibody targets. The extracellular mucin MUC1 is overexpressed and aberrantly glycosylated in many cancers; thus, we evaluated whether autoantibodies generated to aberrant O-glycoforms of MUC1 might serve as sensitive diagnostic biomarkers for cancer. Using an antibody-based glycoprofiling ELISA assay, we documented that aberrant truncated glycoforms were not detected in sera of cancer patients. An O-glycopeptide microarray was developed that detected IgG antibodies to aberrant O-glycopeptide epitopes in patients vaccinated with a keyhole limpet hemocyanin-conjugated truncated MUC1 peptide. We detected cancer-associated IgG autoantibodies in sera from breast, ovarian, and prostate cancer patients against different aberrent O-glycopeptide epitopes derived from MUC1. These autoantibodies represent a previously unaddressed source of sensitive biomarkers for early detection of cancer. The methods we have developed for chemoenzymatic synthesis of O-glycopeptides on microarrays may allow for broader mining of the entire cancer O-glycopeptidome.
Wandall
Hans H
HH
Center for Glycomics, Departments of Cellular and Molecular Medicine and Oral Diagnostics, University of Copenhagen, Blegdamsvej 3, Copenhagen 2200 N, Denmark. hhw@sund.ku.dk
Blixt
Ola
O
Tarp
Mads A
MA
Pedersen
Johannes W
JW
Bennett
Eric P
EP
Mandel
Ulla
U
Ragupathi
Govind
G
Livingston
Phil O
PO
Hollingsworth
Michael A
MA
Taylor-Papadimitriou
Joyce
J
Burchell
Joy
J
Clausen
Henrik
H
D017951:Antigen Presentation / Q000502:physiology; D001323:Autoantibodies / Q000032:analysis* / Q000097:blood; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000276:immunology*; D001943:Breast Neoplasms / Q000097:blood / Q000276:immunology; D002277:Carcinoma / Q000097:blood / Q000276:immunology; D016022:Case-Control Studies; D017321:Clinical Trials, Phase I as Topic; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D018604:Epitope Mapping / Q000379:methods; D000939:Epitopes / Q000032:analysis*; D005260:Female; D006020:Glycopeptides / Q000276:immunology*; D006801:Humans; D007114:Immunization; D008297:Male; D008954:Models, Biological; D018396:Mucin-1 / Q000737:chemistry / Q000276:immunology; D010051:Ovarian Neoplasms / Q000097:blood / Q000276:immunology; D019151:Peptide Library; D011471:Prostatic Neoplasms / Q000097:blood / Q000276:immunology; D040081:Protein Array Analysis / Q000295:instrumentation / Q000379:methods
D001323:Autoantibodies; D014408:Biomarkers, Tumor; D000939:Epitopes; D006020:Glycopeptides; C060192:MUC1 protein, human; D018396:Mucin-1; D019151:Peptide Library