Proteomic mapping of p53 immunogenicity in pancreatic, ovarian, and breast cancers

Purpose Mutations in TP53 induce autoantibody immune responses in a subset of cancer patients, which have been proposed as biomarkers for early detection. Here, we investigate the association of p53‐specific autoantibodies with multiple tumor subtypes and determine the association with p53 mutation...

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Bibliographic Details
Published in:Proteomics. Clinical applications 2016-07, Vol.10 (7), p.720-731
Main Authors: Katchman, Benjamin A., Barderas, Rodrigo, Alam, Rizwan, Chowell, Diego, Field, Matthew S., Esserman, Laura J., Wallstrom, Garrick, LaBaer, Joshua, Cramer, Daniel W., Hollingsworth, Michael A., Anderson, Karen S.
Format: Article
Language:English
Subjects:
Antibody mapping
Antibody Specificity
Autoantibodies - blood
Autoantibodies - immunology
Autoantibody
Breast cancer
Breast Neoplasms - blood
Breast Neoplasms - genetics
Breast Neoplasms - immunology
Cancer
Epitopes - immunology
Female
Humans
Mutation
Ovarian Neoplasms - blood
Ovarian Neoplasms - genetics
Ovarian Neoplasms - immunology
p53
Pancreatic Neoplasms - blood
Pancreatic Neoplasms - genetics
Pancreatic Neoplasms - immunology
Protein array
Proteomics
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - immunology
Tumor Suppressor Protein p53 - metabolism
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Summary:Purpose Mutations in TP53 induce autoantibody immune responses in a subset of cancer patients, which have been proposed as biomarkers for early detection. Here, we investigate the association of p53‐specific autoantibodies with multiple tumor subtypes and determine the association with p53 mutation status and epitope specificity. Experimental design IgG p53 autoantibodies (p53‐AAb), were quantified in 412 serum samples using a programmable ELISA assay from patients with serous ovarian, pancreatic adenocarcinoma, and breast cancer. To determine if patients generated mutation‐specific autoantibodies we designed a panel of the most relevant 51 p53 point mutant proteins, to be displayed on custom programmable protein microarrays. To determine the epitope specificity we displayed 12 overlapping tiling fragments and 38 N‐ and C‐terminal deletions spanning the length of the wild‐type p53 protein. Results We detected p53‐AAb with sensitivities of 58.8% (ovarian), 22% (pancreatic), 32% (triple negative breast cancer), and 10.2% (HER2+ breast cancer) at 94% specificity. Sera with p53‐AAb contained broadly reactive autoantibodies to 51 displayed p53 mutant proteins, demonstrating a polyclonal response to common epitopes. All p53‐AAb displayed broad polyclonal immune response to both continuous and discontinuous epitopes at the N‐ and C‐terminus as well as the DNA‐binding domain. Conclusion and clinical relevance In this comprehensive analysis, mutations in tumor p53 induce strong, polyclonal autoantibodies with broadly reactive epitope specificity.
ISSN:1862-8346
1862-8354
DOI:10.1002/prca.201500096