Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 720-731 |
| Number of pages | 12 |
| Journal | Proteomics - Clinical Applications |
| Volume | 10 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jul 1 2016 |
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Keywords
- Antibody mapping
- Autoantibody
- Cancer
- p53
- Protein array
ASJC Scopus subject areas
- Clinical Biochemistry
Cite this
Proteomic mapping of p53 immunogenicity in pancreatic, ovarian, and breast cancers. / 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.
In: Proteomics - Clinical Applications, Vol. 10, No. 7, 01.07.2016, p. 720-731.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Proteomic mapping of p53 immunogenicity in pancreatic, ovarian, and breast cancers
AU - Katchman, Benjamin A.
AU - Barderas, Rodrigo
AU - Alam, Rizwan
AU - Chowell, Diego
AU - Field, Matthew S.
AU - Esserman, Laura J.
AU - Wallstrom, Garrick
AU - LaBaer, Joshua
AU - Cramer, Daniel W.
AU - Hollingsworth, Michael A.
AU - Anderson, Karen
PY - 2016/7/1
Y1 - 2016/7/1
N2 - 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.
AB - 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.
KW - Antibody mapping
KW - Autoantibody
KW - Cancer
KW - p53
KW - Protein array
UR - http://www.scopus.com/inward/record.url?scp=84978998649&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84978998649&partnerID=8YFLogxK
U2 - 10.1002/prca.201500096
DO - 10.1002/prca.201500096
M3 - Article
VL - 10
SP - 720
EP - 731
JO - Proteomics - Clinical Applications
JF - Proteomics - Clinical Applications
SN - 1862-8346
IS - 7
ER -