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

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.

AAgAtlas 1.0: a human autoantigen database

“…For example, p53 is perhaps one of the most famous AAg whose antibodies are frequently up-regulated in serum or plasma of cancer patients (34). Here, we searched our database with ‘TP53′ and the results revealed that p53 might be involved into more than one hundred different diseases such as liver cancer, neck cancer, lymphoma and rheumatic disease, etc (Supplementary Table S1).…”

The Double Role of p53 in Cancer and Autoimmunity and Its Potential as Therapeutic Target

“…In relation to this phenomenon, p53 Abs were detected in the sera of patients affected by pancreatic adenocarcinoma, serous ovarian and breast cancer [110]. These have been proposed as potential biomarkers for early detection and prognosis [110,111].…”

“…In relation to this phenomenon, p53 Abs were detected in the sera of patients affected by pancreatic adenocarcinoma, serous ovarian and breast cancer [110]. These have been proposed as potential biomarkers for early detection and prognosis [110,111]. In the other studies, immunoreactivity against MDM2 and p53 has also been envisaged as biomarker for the immunodiagnosis of esophageal squamous cell carcinoma [112].…”

Autoantibody biomarkers for the detection of serous ovarian cancer

“…TAAbs are generated in response to protein overexpression or mutations in cancer patients. Our group as well as others have identified panels of TAAbs for the detection of breast [11, 12], prostate [13], colorectal [14], lung [15], and ovarian cancers [16]. In addition to CA 125 and HE4, serum antibodies to p53 are the most frequently studied TAAb in ovarian cancer [4, 17].…”