Article

Cancer Biomarkers Defined by Autoantibody Signatures to Aberrant O-Glycopeptide Epitopes

Center for Glycomics, Departments of Cellular and Molecular Medicine and Oral Diagnostics, University of Copenhagen, Blegdamsvej 3, Copenhagen 2200 N, Denmark.
Cancer Research (Impact Factor: 9.33). 02/2010; 70(4):1306-13. DOI: 10.1158/0008-5472.CAN-09-2893
Source: PubMed

ABSTRACT

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.

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Available from: Eric P Bennett, Jan 09, 2014
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    • "The earlier studies on AGEs and their immunogenicity have also shown AGE-modified proteins acting as endogenous source of innate epitopes recognized by natural antibodies (Chikazawa et al. 2013). Since cancer-associated circulating autoantibodies against protein post-translational modifications are emerging as promising biomarkers for the early detection of cancer, there exists a possibility of autoantibodies against glycated histone proteins in the cancer patients, which may have a significant diagnostic relevance (Wandall et al. 2010). Already, efforts have started to detect autoantibodies presented against aberrantly processed proteins in cancer that are immunogenic and stimulate cellular and humoral immune response on similar lines as that for rheumatoid arthritis, wherein anti-immunogIobulin G (IgG) antibodies have been reported as a diagnostic biomarker (Soussi 2000). "

    Full-text · Dataset · Nov 2015
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    • "The earlier studies on AGEs and their immunogenicity have also shown AGE-modified proteins acting as endogenous source of innate epitopes recognized by natural antibodies (Chikazawa et al. 2013). Since cancer-associated circulating autoantibodies against protein post-translational modifications are emerging as promising biomarkers for the early detection of cancer, there exists a possibility of autoantibodies against glycated histone proteins in the cancer patients, which may have a significant diagnostic relevance (Wandall et al. 2010). Already, efforts have started to detect autoantibodies presented against aberrantly processed proteins in cancer that are immunogenic and stimulate cellular and humoral immune response on similar lines as that for rheumatoid arthritis, wherein anti-immunogIobulin G (IgG) antibodies have been reported as a diagnostic biomarker (Soussi 2000). "
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    ABSTRACT: The role of aberrant protein modifications in cancer has emerged as a promising research field. Non-enzymatic glyco-oxidation of proteins under oxidative stress has been associated with carcinogenesis through AGE-RAGE axis. Modified proteins, that are immunogenic and stimulate cellular and humoral immune responses, are being studied to develop early detection markers of cancer. This study has probed the structural alternations; leading to the formation of adducts and aggregates, in histone H2A upon in-vitro modification by methylglyoxal (MG). The immunogenicity of modified histone H2A and its binding with cancer auto-antibodies was also assessed.Methylglyoxal induced lysine side chain modifications, blocking of free amino groups and the formation of condensed cross structures in histone H2A; and its effect was inhibited by carbonyl scavengers. It led to the adduct formation and generation of N-epsilon-(carboxyethyl)lysine (CEL) and its decomposition forms as revealed by MALDI-MS, HPLC and LCMS. MG-H2A showed amorphous aggregate formation under electron microscopy and altered binding with DNA in CD studies. The modified histone elicited high titre immunogen specific antibodies in rabbits when compared to the native, thus pointing towards the generation of neo-epitopes in MG-H2A. The auto-antibodies derived from cancer patients exhibited enhanced binding with MG-H2A as compared to the native histone in ELISA and gel retardation assay. This reflects sharing of epitopes on MG-H2A and histones in cancer patients. The neo-epitopes on H2A may be responsible for induction and elevated levels of antibodies in cancer patients. Thus, MG-H2A may be considered as potential antigenic candidate for autoimmune response in cancer.
    Full-text · Article · Sep 2015 · Glycobiology
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    • "The altered glycosylation observed in cancer cells leads to the expression of modified tumorassociated glycans (TAG) such as Thomsen-Friedenreich antigen (Galí µí»½1-3GalNAcí µí»¼/í µí»½-O-Ser/Thr; TF, CD176) that may be autoimmunogenic and may be recognized by autoantibodies [1] [2] [3] [4] [5] [6]. TAG are considered as promising targets for cancer immunotherapy [6] [7] [8]. The TF glycotope overexpression observed in the majority of adenocarcinomas and the reduced level of anti-TF antibodies are associated with more aggressive tumors and the induction of invasion, cancer surveillance mechanisms, and patients survival rate [3, 7, 9– 13]. "
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    ABSTRACT: Aim: To study whether alterations in the sialylation of antibodies (Ab) specific to the Thomsen-Friedenreich (TF) glycotope have a diagnostic and prognostic potential in gastric cancer. Methods: Serum samples were taken from patients with gastric carcinoma (n = 142) and controls (n = 61). The level of TF-specific antibodies and their sialylation was detected using ELISA with synthetic TF-polyacrylamide conjugate as antigen and sialic acid-specific Sambucus nigra agglutinin (SNA). Results: The level of TF-specific IgM was significantly decreased in cancer compared with controls (P ≤ 0.001). Cancer patients showed a higher level of SNA binding to anti-TF IgM and IgA (P ≤ 0.001) irrespective of disease stage, tumor morphology, and gender. Changes in the SNA/Ab index demonstrated moderate sensitivity (66-71%) and specificity (60-73%) for stomach cancer. The best diagnostic accuracy (100%) was achieved in 29% patients with high SNA binding and low anti-TF IgM level. This subset of patients demonstrated the poorest survival. Conclusion: Our findings are the first evidence that the increased sialylation of TF-specific Abs combined with a low level of anti-TF IgM is strongly linked to gastric cancer and patients survival, which can be used as a novel biomarker for cancer detection and prognosis.
    Full-text · Article · Sep 2014 · BioMed Research International
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